This document discusses analgesics used in oral and maxillofacial surgery. It begins by introducing different types of analgesics including non-narcotic analgesics like NSAIDs and paracetamol, as well as opioids. It then covers concepts related to pain pathways and mechanisms like nociception, transduction, transmission, perception, and modulation. The remainder of the document delves into further details of various opioid and non-opioid analgesics, how they work, their uses, receptors, and endogenous opioid peptides.
This set of 17 slides introduces students to the some of the basic physiological processes that are the targets of many analgesic drug classes. It is suitable for beginner/intermediate level learners.
This set of 17 slides introduces students to the some of the basic physiological processes that are the targets of many analgesic drug classes. It is suitable for beginner/intermediate level learners.
seminar is about the mechanism of action of the central and periphary acting analgesics. the pathway of pain and various analgesic and their properties
Pain management strategies & effects on wellbeingmiranda olding
Overview of pain, common pain management strategies and their effects on wellbeing. Side effects, effects on wellbeing, Covers Pain cycle, Persistent or chronic pain, pain gate theory, pharmaceutical and non-pharmaceutical or pain treatments, including complementary therapies, electrotherapies, psychological therapies for pain.
Written for student OT conference 'Perspectives on Wellbeing' Feb 2016
objectives of this lecture are Compare the characteristics of acute pain, chronic pain, and cancer pain.
Describe factors that can alter the perception of pain.
Describe the pathophysiology of pain.
Describe the use of pain measurement instruments.
Identify appropriate pharmacologic and non-pharmacologic pain management.
Analgesics general dentistry /certified fixed orthodontic courses by Indian d...Indian dental academy
Welcome to Indian Dental Academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.
Indian dental academy has a unique training program & curriculum that provides students with exceptional clinical skills and enabling them to return to their office with high level confidence and start treating patients
State of the art comprehensive training-Faculty of world wide repute &Very affordable.
seminar is about the mechanism of action of the central and periphary acting analgesics. the pathway of pain and various analgesic and their properties
Pain management strategies & effects on wellbeingmiranda olding
Overview of pain, common pain management strategies and their effects on wellbeing. Side effects, effects on wellbeing, Covers Pain cycle, Persistent or chronic pain, pain gate theory, pharmaceutical and non-pharmaceutical or pain treatments, including complementary therapies, electrotherapies, psychological therapies for pain.
Written for student OT conference 'Perspectives on Wellbeing' Feb 2016
objectives of this lecture are Compare the characteristics of acute pain, chronic pain, and cancer pain.
Describe factors that can alter the perception of pain.
Describe the pathophysiology of pain.
Describe the use of pain measurement instruments.
Identify appropriate pharmacologic and non-pharmacologic pain management.
Analgesics general dentistry /certified fixed orthodontic courses by Indian d...Indian dental academy
Welcome to Indian Dental Academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and offering a wide range of dental certified courses in different formats.
Indian dental academy has a unique training program & curriculum that provides students with exceptional clinical skills and enabling them to return to their office with high level confidence and start treating patients
State of the art comprehensive training-Faculty of world wide repute &Very affordable.
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.
Opioids are a class of drugs that include the illegal drug heroin, synthetic opioids such as fentanyl, and pain relievers available legally by prescription, such as oxycodone (OxyContin®), hydrocodone (Vicodin®), codeine, morphine, and many others. Learn about the health effects of prescription opioids and read the DrugFacts on Fentanyl, Heroin, and Prescription Opioids.
Opioid-involved overdose deaths rose significantly from 46,802 deaths in 2018 to 49,860 in 2019.
Source: National Vital Statistics System, CDC
Looking for Treatment?
Use the SAMHSA Treatment Locator or call 1-800-662-HELP (4357).
Learn more about:
NIDA's Role in the NIH HEAL Initiative℠
Overdose Death Rates
Benzodiazepines & Opioids
Xylazine in the Illicit Opioid Supply
Opioid Research Findings Funded by NIDA - (PubMed - 2001 to present)
Definition n classification •Pathophysiologyof pain. •Physiological Effects of pain. •Pharmacological & non-pharmacological methods of analgesia. •Principles of pain management.METHODS OF CONTROLLING METHODS OF CONTROLLING
Non-pharmacological Preoperative counseling TENS Acupuncture
Pharmacological Opioids •Im •IV infusion •IV PCA Local anaesthetics: •Local Infiltration •Nerve Blocks •Epidural Blocks NSAIDS •IM •IV infusion •IV PCA
NON-PHARMACOLOGICAL METHODS PRE-OP COUNSELLING: Well informed patients about: •Nature of operation •Nature of post operative pain •Methods of analgesia available
Cope better with Post –op Pain
NON-PHARMACOLOGICAL METHODS TENS (Trans Cutaneous electric nerve stimulation)
Stimulates afferent myelinated (A-beta) nerve fibers at 70hz
Inhibitory circuits within sp cord activated
Nerve impulse transmission reduced
Maximum benefit in neurogenic pain
PHARMACOLOGICAL METHODS OPIODS •Activate opiodreceptors within the CNS •Reduce transmission of nerve impulses by modulation in the dorsal horn
PHARMACOLOGICAL METHODS
LOCAL ANAESTHETICS –Blocks the conduction of nerve impulses –Can be given with adrenaline because •Decreases absorption of L.A allowing larger doses •Also acts on alpha 2 receptors which potentiates analgesic effect
PHARMACOLOGICAL METHODS
NASIDS –Blocks synthesis of PG’s –Only suitable for miledto moderate pain
PRINCIPLE OF MANAGEMENT OF PAIN •Pre-emptive analgesia •Balanced or combination analgesia •Analgesia ladder
PHARMACOLOGICAL METHODS
Balanced Analgesia –NASID are used in conjunction with opioids. –Reduces amount of opioids –Reduces side affect of opioids,ASSESMENT OF PAIN •Observe the behaviour of the patient •Monitor analgesic requirement of the patient –Visual Analogue Score( VAS )
–Verbal Rating Score ( VRS ) •None •Mild •Moderate •severe
this seminar consists of pain,components of pain,pain pathways - ascending and analgesic followed by management of dental pain and local anesthesia,composition,various techniques used and pediatric implications for the administration of the locan anesthetics and the newer agents wich are available in topical,injectable and intra osseous techniques
Opportunity for Dentists (BDS/MDS )to relocate to United kingdom -Register as a DENTAL HYGIENIST/ DENTAL THERAPIST without Board exams and after approval you can register in GDC as a DH/DT and start working as a DH/DT Immediately and get paid.
You can complete the whole process in 3-4 months.Salary range for DH/DT is around 2500-3500 Pounds per month.
Eligibility / requirements-
1. An International English Language Testing System (IELTS) certificate
at the appropriate level.(Within 2 yrs of application date )
2: A recent primary dental qualification that has been taught and examined in English..(Within 2 yrs of application date )
3: A recent pass in a language test for registration with a regulatory authority in a country where the first language is English.
If you are interested Please contact us for more details.
1ST, 2ND AND 3RD ORDER BENDS IN STANDARD EDGEWISE APPLIANCE SYSTEM /Fixed ort...Indian dental academy
Indian Dental Academy: will be one of the most relevant and exciting training center with best faculty and flexible training programs for dental professionals
who wish to advance in their dental practice,Offers certified courses in Dental implants,Orthodontics,Endodontics,Cosmetic Dentistry, Prosthetic Dentistry,
Periodontics and General Dentistry.
Indian Dental Academy: will be one of the most relevant and exciting training center with best faculty and flexible training programs for dental professionals who wish to advance in their dental practice,Offers certified courses in Dental implants,Orthodontics,Endodontics,Cosmetic Dentistry, Prosthetic Dentistry, Periodontics and General Dentistry.
I –Aligners are made with FDA approved transparent thermoplastic materials using 3D scanning, 3D Printing and finally Trays with Pressure vacuum formers.
Dear Doctor,
Indian Dental Academy Now offers comprehensive online Orthodontics course.
Course includes:
1.whiteboard lecture presentations
2.Case Discussions
3.with hundreds of pictures.
4.Demo on Models
5.Demo on Patients
6. subtitles in your own language
12 months unlimited access and support @350 USD only.
For Demo please visit :www.idalectures.com/preview/
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Thanks & Regards
Indian Dental Academy
--
Indian Dental Academy
Leader in continuing dental education
www.indiandentalacademy.com
skype:indiandentalacademy
+919248678078
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
Cytotoxicity of silicone materials used in maxillofacial prosthesis / dental ...Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
Diagnosis and treatment planning in completely endntulous arches/dental coursesIndian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
Properties of Denture base materials /rotary endodontic coursesIndian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
Use of modified tooth forms in complete denture occlusion / dental implant...Indian dental academy
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
The Indian Dental Academy is the Leader in continuing dental education , training dentists in all aspects of dentistry and
offering a wide range of dental certified courses in different formats.for more details please visit
www.indiandentalacademy.com
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...
Analgesics in oral surgery/rotary endodontic courses by indian dental academy
1. GITAM DENTAL COLLEGE & HOSPITAL
DEPARTMENT OF
ORAL AND MAXILLOFACIAL SURGERY
SEMINAR ON
ANALGESICS IN ORAL AND MAXILLOFACIAL SURGERY
PRESENTED BY
DR.NAGA MALLESWAR RAO.I (I MDS)
2. ANALGESICS IN ORAL AND MAXILLOFACIAL SURGERY
INTRODUCTION:
Pain is one of the most common reasons patients seek dental treatment. It may
be due to many different diseases/conditions or it may occur after
treatment. Dentists must be able to diagnose the source of pain and have
strategies for its management. The ‘3-D’s’ principle – diagnosis, dental treatment
and drugs – should be used to manage pain. The first, and most important, step is
to diagnose the condition causing the pain and identify what caused that
condition. Appropriate dental treatment should then be undertaken to remove
the cause of the condition as this usually provides rapid resolution of the
symptoms. Drugs should only be used as an adjunct to the dental treatment.
Most painful problems that require analgesics will be due to inflammation. Pain
management drugs include non-narcotic analgesics
(e.g., non-steroidal anti-inflammatory drugs, paracetamol, etc) or opioids (i.e.,
narcotics). Nonsteroidal anti-inflammatory drugs (NSAIDs) provide excellent pain
relief due to their anti-inflammatory and analgesic action. The most common
NSAIDs are aspirin and ibuprofen. Paracetamol gives very effective analgesia but
has little anti-inflammatory action. The opioids are powerful analgesics but have
significant side effects and therefore they should be reserved for severe pain only.
The most commonly used opioid is codeine, usually in combination with
paracetamol. Corticosteroids can also be used for
managing inflammation but their use in dentistry is limited to a few very specific
situations.
AIM:
The aim of this seminar is to understand the concepts of pain and various drugs
that are used to relieve pain, their actions, adverse effects, principles of analgesic
use, indications, contraindications of different types of analgesics and their
interactions.
CONCEPTS OF PAIN:
The word pain is derived from the latin word “poena” which means punishment.
The International Association for the Study of Pain (IASP) has proposed the
following working definition: pain is ‘an unpleasant sensory and emotional
experience associated with either actual or potential tissue damage, or described
in terms of such damage’. Pain affects every category of patient care. Whether
3. the issue is wound care, a painful joint, an irritated skin condition, or an endocrine
disorder, understanding the pathway of pain will help the practitioner in
assessment and management of the patient in pain. The pain pathway can be
broken into categories to clarify the pain process. Nociception, Transduction,
Transmission, Perception, and Modulation are concepts that are basic to
understanding the pain pathway.
NOCICEPTION:
Nociception refers to the process by which information about tissue damage is
transmitted from peripheral receptors to the peripheral nervous system and onto
the central nervous system. The first step in the pain pathway is the transduction
of noxious stimulation into nerve signals that will travel up ascending pathways to
the brain. Nociceptors are free, primary afferent nerve endings in cutaneous,
muscle, and visceral tissues. Nociceptors can respond in one of two ways. They
can respond to the actual noxious stimulation or they
can respond to the changes in surrounding tissues caused by the noxious
stimulation. Noxious stimulation can cause cellular damage that precipitates
cellular changes, including the release of numerous chemicals, enzymes,
mediators, ionic changes, pHchanges, and catalyzing the inflammatory
cascade. Histamine and serotonin release increase vasodilation and inflammation.
TRANSDUCTION:
Transduction is the conversion of energy from a noxious thermal, mechanical
or chemical stimulus into nerve impulses (electrical energy) by nociceptors.
Stimuli evoke changes in the integrity of neural membranes of the nociceptors,
producing inward sodium and calcium currents, causing the basic action potential
that initiates a nerve impulse.
TRANSMISSION:
Transmission is the process where neural signals from the site of transduction are
transmitted to the spinal cord and brain. After the nerve impulse is created, the
nociceptive impulse is transmitted from the free nerve endings along stimulus-
specific nerve fibers. This is the first order nociceptive
primary afferent nerve fiber consisting of A-delta fibers and C-fibers. Each carries
different types of input and are responsible for different subjective
perceptions. A-delta fibers are small, thinly myelinated neurons. “First Pain” is the
initial sensation of pain described as sharp, localized and well defined. Adelta
fibers are modality specific. They respond to extremes of temperature,
high intensity mechanical stimulation, light and deep pressure, stab and pinch.
4. C-fibers are small, unmyelinated afferent nerves. The absence of myelin leads to
slower conducting velocity. “Second Pain” is a diffuse, poorly localized, burning,
throbbing or gnawing sensation after the initial sensations of “first pain.” Second
pain is temporally and qualitatively distinct from first pain.
Quantitatively, the majority of nociceptive afferent nerve fibers in the cutaneous
tissues are C-fibers. Cfibers are polymodal; they can be activated
by any combination of thermal, mechanical or chemical stimulation.
C-fiber thresholds for stimulation are easily sensitized, accounting for persistent
pain and hyperalgesia. C-fibers also innervate muscle tissue, tendons and areas
surrounding vascular walls. In addition to nociceptive initiation of the pain
pathway into the primary afferent nerve, neurogenic
stimulation can also initiate impulses into the pain pathway.
NEURON TO NEURON:
The next step in the pain pathway is the passing of the nerve impulse from the
primary afferent neuron to the second order neuron in the spinal cord for
transmission to the brain. The spinal cord has a ventral and a dorsal root. About
40% of afferent nociceptive nerves synapse in the ventral spinal cord. The vast
majority of cutaneous and visceral nociceptive afferent fibers project to the dorsal
horn of the spinal cord. The dorsal horn is anatomically divided
into ten zones called laminae of Rexed and these laminae are numbered
consecutively. Both A-delta fibers and C-fibers end on specific second order
neurons in the laminae I, II, IIa, and V of the dorsal horn of the spinal cord. This is
the origin of the ascending pathway of the second order neurons to the brain.
NEUROCHEMICAL MEDIATION:
The principle neurochemical mediator at the synaptic cleft between the primary
afferent neuron and the dorsal horn cells is glutamate. The primary afferent
neurons also release a chemical called substance-P which binds to receptors post-
synaptically. The dorsal horn of the spinal cord is a critical site for convergence
and neural processing of nociceptive information. The second order neurons
aggregate in the dorsal horn, project contralaterally and ascend to the brain in
bundles called ascending tracts. Some second order neurons ascend in the
spinothalmic tract to the brainstem, midbrain and thalamus.
Others ascend to higher brain centers via the spinoreticular tracts.
GATE CONTROL THEORY:
The “gate control” theory of pain involves the convergence of first order neurons
at the dorsal horn. Unpleasant impulses entering the dorsal horn via C-fibers can
5. be suppressed by concurrent stimulation of A-delta fibers or by impulses passing
through A-beta fibers. This is the basis for acupuncture and
for transcutaneous electrical nerve stimulation (TENS). In summary, first pain is
punctuate, well localized and temporally defined. It is a function of nociceptive
stimulation of rapidly conducting A-delta primary afferent fibers that synapse in
the dorsal horn of the spinal cord with second order neurons. Second pain is more
diffuse, longer lasting. It is nociceptive sensation that follows the initial
stimulus and is the result of slower conducting C-fibers transmitting signals to the
dorsal horn of the spinal cord. Neurotransmitters mediate transmission
of pain in the spinal cord and the brain. There are many neurotransmitters and
more are being discovered. They can be categorized as: excitatory
neurotransmitters, such as glutamate and tachykinins, inhibitory transmitters,
such as gamma amino butyric acid (GABA), and neurotransmitters associated with
descending pain transmission, such as noradrenalin, serotonin and opiates.
PERCEPTION:
The perception of pain is an uncomfortable awareness of some part of the body,
characterized by a distinctly unpleasant sensation and negative emotion best
described as threat. Both cortical and limbic system structures are involved.
MODULATION:
Modulation is the descending inhibitory and facilitory input from the brain
influencing nociceptive transmission at the level of the spinal cord. Modulation
actually occurs at many levels, but historically it has been considered only as the
attenuation of ascending dorsal horn transmission by descending inhibitory input
from the brain. Multiple brain regions contribute to this descending inhibition.
Impulses from these brain centers descend and cause the release of inhibitory
substances at the dorsal horn of the spinal cord. Some of these inhibitory
substances include endogenous opioids, serotonin, norepinephrine and GABA.
These inhibitory substances bind on receptors on either the primary afferent
neurons or the dorsal horn secondary neurons to inhibit transmission of the
nociceptive impulse from the primary afferents to the secondary neurons in the
dorsal horn. This endogenous modulation accounts for the wide variations in pain
perception in patients with similar injuries. Neurons of the sensory cortex of the
brain can exert inhibitory control over the other neural pathways inside the brain
itself. Cortical inhibition can normalize or stabilize afferent neural signals. The
cortical neurons can also excite the lower brain pain pathways. Therefore, cortical
neurons can discriminately amplify or reduce the afferent pain input to the brain.
In addition to the descending effects of the brain and brainstem, pain modulation
6. also occurs at the spinal cord level. Activation of local circuits within the spinal
dorsal horn modulates pain. This is one of basics of the “gate theory” of pain.
SENSITIZATION:
There are two types of sensitization in the pain pathways, peripheral sensitization
and central sensitization. With peripheral sensitization, sensitized nociceptors
exhibit a lower threshold for activation and an increased rate of firing.
Inflammatory mediators, intense, repeated, or prolonged noxious stimulation, or
both can sensitize nociceptors. Sensitized nociceptors generate nerve impulses
more readily and more often.
AN
7. ANALGESICS:
A drug that selectively relieves pain by acting in the CNS or on the peripheral pain
mechanism, without significantly altering consciousness is called an analgesic.
Analgesics are classified as
1. CENTRALLY ACTING (OR) OPIOID ANALGESICS
2. PERIPHERALLY ACTING (OR) NON OPIOID ANALGESICS
OPIOID ANALGESICS:
8. The opium poppy is the source of crude opium from which Serturner in 1803
isolated the pure alkaloid morphine—named after Morpheus, the Greek god of
dreams. It remains the standard against which all drugs that have strong analgesic
action are compared. These drugs are collectively known as "opioid analgesics"
and include not only the natural and semisynthetic alkaloid derivatives from
opium but also include synthetic surrogates, other opioid-like drugs whose
actions are blocked by the nonselective antagonist naloxone, plus several
endogenous peptides that interact with the several subtypes of opioid
receptors...." Morphine, the prototypical opioid agonist, has long been known to
relieve severe pain with remarkable efficacy. The importance of the first use of
opioids in developing drug dependence of the opioid type was discussed. Seven
major factors were clinically observed to influence first heroin use. The factors are
diminished self-esteem, interpersonal strivings, proselytizing, ignorance of opioid
effects, pleasure, transquilization and pain. More than one factor is usually
operative in a particular instance. Ready availability of opioids is usually essential
to first use, even when the described factors are present. An understanding of
these determinants should improve educational efforts
aimed at prevention of opioid drug use. The expert panel concluded that opioid
pain medications are safe and effective for carefully selected, well-monitored
patients with chronic non-cancer pain. Opioid prescribing has increased
significantly due to growing professional acceptance that the
drugs can relieve chronic non-cancer pain, and the guideline acknowledges there
are widespread concerns about increases in prescription opioid abuse, addiction
and diversion. Opioids, such as morphine, oxycodone, oxymorphone and fentanyl
are potent analgesics. They traditionally have been used to relieve pain following
surgery, from cancer and at the end of life. Today opioids are used widely to
relieve severe pain caused by chronic low-back injury, accident trauma, crippling
arthritis, sickle cell, fibromyalgia, and other painful conditions. Prior to initiating
chronic opioid therapy, the guideline advises clinicians to determine if the pain
can be treated with other medications. If opioids are appropriate, the clinician
should conduct a thorough medical history and examination and assess potential
risk for substance abuse, misuse or addiction.
Opioids are powerful pain-relieving substances that are used as analgesics, or pain
medications. They come from one of three places, some are derived from plants,
some are manufactured in a lab and others, such as endorphins, occur naturally in
the body. Opioids act by attaching to specific proteins called opioid receptors,
which are found in the brain, spinal cord, and gastrointestinal tract. When these
9. compounds attach to certain opioid receptors in the brain and spinal cord, they
can effectively change the way a person experiences pain
Opioids are very effective in the treatment of severe pain. In fact, they are
frequently used to treat acute pain, such as post-surgical pain, as well as severe
pain caused by diseases such as cancer. While opioid use for the long-term
treatment of chronic pain is still somewhat controversial, these drugs can be
effective and safe when taken under close medical supervision. Some opioids,
such as oxycodone and hydromorphone, are straight narcotics. Others, such as
codeine and hydrocodone, may be mixed with other analgesics such as
acetaminophen. Another class of opioids, defined as agonist/antagonist, combine
medications to decrease pain and to decrease the potential for dependence.
These include buprenorphine and butorphanol. Unfortunately, many chronic pain
sufferers who take opioids may wrongly be labeled as addicts, even if they do not
meet the actual criteria for addiction. There is sometimes a certain stigma
associated with taking narcotic pain medication, which can be frustrating for the
person with severe chronic pain.
In addition, opioid medications can affect regions of the brain that mediate what
we perceive as pleasure, resulting in the initial euphoria that many opioids
produce. They can also produce drowsiness, cause constipation, and, depending
upon the amount taken, depress breathing. Taking a large single dose could cause
severe respiratory depression or death. Opioids may interact with other
medications and are only safe to use with other medications under a physician's
supervision. Typically, they should not be used with substances such as alcohol,
antihistamines, barbiturates, or benzodiazepines. Since these substances slow
breathing, their combined effects could lead to life threatening respiratory
depression.
USES - Used for thousands of years to produce:
– Euphoria
– Analgesia
– Sedation
– Relief from diarrhea
– Cough suppression
OPIOIDS RECEPTORS
There are 4 types of opioid receptors, with multiple receptor subtypes:
Mu- These receptors produce the most profound analgesia, and can cause
euphoria, respiratory depression, physical dependence and bradycardia. They are
responsible for most of the analgesic effect of opioid.
10. Kappa – These contribute to analgesia at the spinal level. These receptors trigger
a lesser analgesic response, and may cause miosis, sedation and dysphoria.
Delta – These receptors modulate mu receptor activity and are more important in
the periphery.
Sigma – These receptors provide little to no analgesia. They are responsible for
many of the adverse effects associated with opioids (dysphoria, hallucinations,
respiratory and vasomotor stimulation). Some investigators classify sigma
receptors as phencyclidine, rather than opioid, receptors.
ENDOGENOUS OPIOID PEPTIDES:
A number of peptides having morphine like actions were isolated from the
mammalian brain, pituitary, gastro intestinal track and spinal cord. These are
active in very small amount, their action are blocked by naloxone and the bind
with high affinity with the opioid receptors. There are three families of opioid
peptides. Each is derived from a specific large precursor polypeptides.
Endorphins - beta-endorphin is having 31 amino acids, is the most important of
the endorphins. It is derived from the Pro-opiomelanocortin (POMC) which also
gives rise to ACTH and two lipoproteins. b-endorphin is primarily mu agonist but
also has delta action·
Enkephalins - Methionie-enkephalin(met-ENK) and leucine-enkephalin (leu-ENK)
are the most important. Both are pentapeptides. The larger precursor peptide
proenkephalin has 4 met-ENK and 1 leu-ENK residues. The two ENKs have a
slightly different spectrum of activity, while met-ENK has equal affinity for mu and
delta sites, leu-ENK prefer delta receptors.
Dynorphins - Dynorphin A and B (DYN-A and DYN-B) are 8-17 amino acid peptides
derived from prodynorphin which contains 3 leu-ENK residues. DYN are more
potent on kappa receptors but also activate mu and delta receptors.
CLASSIFICATION OF OPIOID ANALGESIC DRUGS:
STRONG AGONISTS:
Morphine, mepiridine, methadone, fentanyl.
MODERATE AGONISTS:
Propoxyphene, codeine
MIXED AGONISTS-ANTAGONISTS:
Pentazocine, nalbuphine, buprenorphine.
ANTAGONISTS:
Naloxone: it rapidly displaces opioids from receptors with in 30 secs of IV
injection, reverses the respiratory depression and coma due to heroin overdose,
11. competitive antagonist for mu, delta and kappa receptors with a 10 fold higher
affinity for mu than for kappa receptors.
MECHANISM OF ACTION OF OPIOIDS:
Produce inhibition of neuronal activity.
Inhibit release of neurotransmitters.
Activate descending inhibitory systems.
PHARMACOLOGICAL ACTIONS:
Analgesia
Euphoria
Nausea and vomiting
Mental confusion
Respiratory depression
Sedation
Pupillary constriction
Constipation
Decreased urinary production(increase ADH secretion)
Precipitates asthma (high doses).
THERAPEUTIC INDICATIONS:
Acute and chronic pain.
Pre-anesthetic medication(fentanyl derivatives)
Dysponea
Dysentry and diarrhoea.
Cough supression
CONTRAINDICATIONS:
Decreased respiratory reserve(emphysema, asthama)
Head injury
Biliary colic
Hepatic insufficiency
Decreased blood volume
Convulsant states
ACUTE TOXICITY:
Severe toxicity- 30-120mg (oral) of morphine
LETHAL DOSE:
Highly variable- >120mg of morphine
Symptoms:
1. Profound coma
12. 2. Depressed respiration
3. Pin point pupils
4. Decreased blood pressure
5. Low body temperature
6. Decreased urine formation
TREATMENT: ventilation( do not administer 100% oxygen because it produces
apnea), naloxone will reverse toxic symptoms.
CHRONIC TOXICITY: Tolerance and physical dependance are manifestations of
chronic toxicity.
Tolerance develops to analgesia, euphoria, sedation and nausea.
Tolerance does not develop to respiratory depression, constipation, miosis.
Physical dependance: Abnormal physical state in which drug must be
administered to maintain normal function.
Physical dependance is manifested by withdrawl symptoms when administration
of the drug is stopped.
Symptoms: 8-12 hrs- lacrimation, rhinorrhea, sweating, yawning.
12-14 hrs- restless sleep
48-72 hrs- dilated pupils, anorexia, irritability, tremors, intestinal
spasm and muscle spasm.
Physiologic effects of opioids
Respiratory effects
All opioids depress minute ventilation by depressing the response of the brain to
carbon dioxide. Opioids primarily reduce respiratory rate, although in high doses
they can also depress tidal volumes. Respiratory depression, apnea and even
death may occur. However, when prescribed and administered for pain in a
properly monitored patient, opioids rarely cause respiratory depression. Fear of
inducing respiratory depression should never be used as a reason to avoid
treating pain. Opioids are also potent antitussives.
Gastrointestinal effects
Opioids universally decrease GI motility by reducing peristalsis in the small
intestine and large intestine, and by increasing tone in the pyloric sphincter,
ileocecal valve, and anal sphincter. Thus, opioid use is associated with
constipation. These agents were first used for the treatment of diarrhea
(dysentery). When these agents are prescribed for longer than 1 or 2 days,
stimulant laxatives and stool softeners are necessary. Unlike other opioid-induced
adverse effects, tolerance to constipation does not develop over
13. time. All μ-agonist opioids, including meperidine, can cause spasms of the
sphincter of Oddi. This effect can be problematic in patients with pancreatitis,
cholelithiasis, or sickle cell disease. Opioids are also associated with nausea and
vomiting, which are caused by the binding of opioids to receptors in the
chemoreceptor trigger zone of the brainstem and by slowed GI motility. Drug
treatment of nausea and vomiting differs according to the cause. If caused by
stimulation of the chemoreceptor trigger zone, ondansetron, prochlorperazine,
thiethylperazine or haloperidol may be helpful. If caused by slowed GI motility,
metoclopramide may be helpful. Nalbuphine (a mixed opioid agonist antagonist)
or a lowdose infusion of naloxone (an opioid antagonist) are also useful in the
treatment of nausea and vomiting. For nausea associated with motion (often
accompanied by vertigo), dimenhydrinate may be helpful.
Scopolamine patches are sometimes used for nausea associated with motion but
may cause confusion.
Cardiovascular effects
Opioids have few hemodynamic adverse effects. They do not affect the
contractile state of the heart or alter cardiac output. All opioids can cause dose-
dependent, asymptomatic bradycardia, with the exception of meperidine, which
produces tachycardia. Morphine is a vasodilator and venodilator. It affects
preload and afterload by relaxing vascular smooth muscle and by releasing
histamine from mast cells. These actions may produce hypotension, especially in
hypovolemic (e.g., trauma) patients. Histamine release occurs to a lesser extent
with codeine and meperidine, and not at all with hydromorphone, fentanyl,
sufentanil or remifentanil. The hypotensive effects of the opioids can be
minimized by slow infusion, keeping patients supine, and maintaining an
adequate intravascular volume.
Genitourinary effects
Opioids increase the tone of the detrussor muscle of the bladder and may cause
urinary retention, which may require bladder catheterization. This adverse effect
may occur regardless of the route of opioid administration but is more common
after neuraxial administration.
Physiologic dependence
Sudden cessation of opioid medication after continued therapy may lead to the
development of abstinence syndrome or withdrawal. Symptoms include
tachycardia, lacrimation, yawning, sneezing, coryza, nausea, vomiting,
hypertension, restlessness, and insomnia. Physiologic dependence can develop
14. after only 5 days of therapy. Symptoms typically occur within 24 hours and peak
about 72 hours after discontinuation of opioid therapy. Tolerance and withdrawal
seem to be linked. Note the difference between physiologic
dependence and addiction, which is a behavioral effect of opioids (see below).
Tolerance
Continued exposure to opioids often results in the need for higher doses to
achieve the same clinical effect. This phenomenon is known as tolerance and
usually begins within 21 days after beginning opioid therapy. Shorter-acting, more
lipophilic agents, such as fentanyl, may lead to tolerance faster than longer-
acting, hydrophilic agents, such as morphine. On the other hand, results from
animal studies suggest that tolerance develops less frequently with opioids that
have high receptor affinity, such as sufentanil. Some degree of cross-tolerance
occurs between opioids, although it is incomplete. Patients who are becoming
tolerant to morphine may benefit from a change to a drug with increased binding
affinity, such as hydromorphone. Tolerance develops more quickly when
continuous infusions, rather than intermittent boluses, are used.
Behavioral effect of opioids
Addiction is defined by the World Health Organization as “A state, psychologic
and sometimes also physical, resulting from the interactions between a living
organism and a drug, characterized by behavioral and other responses that
always include a compulsion to take the drug on a continuous or periodic basis in
order to experience its psychic effects, and sometimes to avoid the discomfort of
its absence. Tolerance may or may not be present.” Addiction is a psychiatric
disorder associated with excessive self-medication against medical advice and
compulsive, often criminal, acquisition of drug. It should not be a concern for the
acute postoperative patient receiving opioids for a short, determinable period.
Commonly used opioids in postoperative pain
The opioids commonly used in the treatment of postoperative pain can be
classified as pure agonists or mixed agonist-antagonists. A pure agonist has
maximal physiologic effect at the binding site (e.g., morphine). An antagonist
occupies the site but has no physiologic action (e.g., naloxone). A partial
agonist occupies the site but has submaximal physiologic activity even at high
doses (e.g., buprenorphone). A mixed opioid agonist-antagonist has agonist
effects at some receptors and antagonist effects at others (e.g., nalbuphine).
Tramadol is a centrally acting synthetic analgesic chemically unrelated to opiates;
15. however, it is also considered to be an opioid because of its agonist activity at μ
receptors.
Pure agonists
1. Morphine
Morphine is the gold standard against which all other opioids are compared. It is
the most widely used opioid for the management of acute pain in adults.
Morphine is hydrophilic and does not cross the bloodbrain barrier well. It also has
poor oral bioavailability (20% to 30%), which necessitates a larger oral (PO)
dose when converting from parenteral to enteral routes of drug administration. In
addition to PO, intravenous (IV), intramuscular (IM), and subcutaneous (SC)
routes, morphine can be administered by epidural and intrathecal routes using
preservative-free formulations. Morphine is metabolized in the liver by
microsomal mixed-function oxygenases that require the P-450 system. Two
metabolites are morphine- 6-glucuronide (which is active and more potent than
morphine) and morphine-3-glucuronide (which is
inactive but competes competitively with morphine at binding sites). These
metabolites are excreted renally, so morphine (and opioids that are metabolized
to morphine, e.g., codeine) must be used with caution in patients with renal
failure because the active metabolite accumulates in the blood. Morphine induces
histamine release and must be used carefully in patients with asthma or atopy.
Histamine release also causes vasodilatation and may produce hypotension in
hypovolemic patients.
2. Meperidine
Meperidine has one-tenth the analgesic potency of morphine and may have a
shorter duration of analgesia (2 to 4 h vs. 2 to 7 h for morphine IM). At equipotent
doses, it has an adverse effect profile similar to that
of morphine. It offers no advantages over morphine in terms of sphincter of Oddi
spasms, bowel motility, or respiratory depression. Meperidine produces a “rush”
or euphoric feeling that some patients enjoy and thus label meperidine as the
“most” effective opioid for them. The primary metabolite of meperidine, by
hepatic N-demethylation, is normeperidine. This compound has half the analgesic
activity of meperidine, is renally eliminated, and can cause hallucinations,
agitation, and seizures. Regular dosing or high doses in patients with normal or
impaired renal function may result in accumulation of normeperidine. Seizures
can be seen at doses of 10 mg/kg/d IV, IM, or SC. It is difficult to identify patients
at risk for meperidine-induced seizures.
16. Patients who concomitantly take meperidine and monoamine oxidase inhibitor
(MAOI) antidepressants may develop a potentially fatal drug interaction. Because
of the long half-life of MAOIs, patients who have discontinued these agents within
the previous two weeks are also at risk. The drug interaction may
cause a serotonin-like syndrome—a life-threatening condition manifested by
hyperpyrexia, acidosis, shock, and death. Because of the toxic metabolite and
potentially fatal drug-drug interaction with MAOIs, one should rarely prescribe
meperidine for acute (or chronic) pain. The Working Group does not recommend
the use of meperidine in the treatment of postoperative pain; longer-acting and
safer opioids are available. If meperidine is indicated (e.g., for the rare patients
with hypersensitivity to opioids from another class), its use should be restricted to
the recovery room or limited to less than 24 hours in doses less than 600 mg / 24
h.
3. Fentanyl
Fentanyl is highly lipid soluble, equilibrates rapidly at the effector site, and has no
active metabolites. Fentanyl can be administered by the IV, IM, SC, transmucosal,
and transdermal route. It is most commonly used for short, painful procedures;
however, it also can be used for postsurgical and burn pain
relief. In general, a dose of fentanyl, 0.5 to 2.0 μg/kg/h, is appropriate whether
given intermittently or by continuous infusion. Transdermal fentanyl is
contraindicated for acute pain management.
4. Hydromorphone
Hydromorphone is sevenfold to tenfold more potent than morphine, and twofold
to sevenfold more lipid soluble. It is metabolized to hydromorphone-3-
glucuronide, which lacks analgesic effect but has been associated with
neurotoxicity. The elimination half-life is 2 to 3 hours. It is typically associated
with fewer adverse effects (e.g., nausea, vomiting, and pruritus) than morphine.
Like morphine, it is versatile and can be administered by the IV, SC, PO, epidural,
or intrathecal routes.
5. Codeine, oxycodone, and hydrocodone
Codeine, oxycodone, and hydrocodone are opioids that are commonly used to
treat pain in children and adults, especially for less severe pain or when treatment
is being converted from parenteral opioids to enteral ones. Codeine, oxycodone,
and hydrocodone are most commonly administered by the PO route, usually in
combination with acetaminophen or aspirin. About 10% of administered codeine
is metabolized to morphine, which is responsible for most if not all of codeine’s
analgesic and antitussive effects. With all combination preparations, physicians
17. should beware of inadvertently administering hepatotoxic doses of
acetaminophen when increasing doses for uncontrolled pain; all sources of
acetaminophen should be considered. Acetaminophen toxicity may result from a
single toxic dose (e.g., 5.85 g), from repeated ingestion of large doses of
acetaminophen (e.g., in adults, 7.5 to 10.0 g/d for 1-2 d; in children, 60 to 420
mg/kg/d for 1 to 42 d) or from chronic ingestion. The recommended maximal
daily dose for acetaminophen is 4 g/d in adults with normal hepatic function and
2 g/d in chronic alcoholics.
Mixed opioid agonist-antagonists
Mixed opioid agonist-antagonists produce analgesia primarily at the κ receptor.
They have a ceiling effect and produce limited respiratory depression. In patients
who are physiologically dependent on opioids, these drugs can induce withdrawal
symptoms. One of the most useful indications for opioid agonistantagonists is
treatment of opioid-induced adverse effects, including nausea and vomiting,
sedation, and pruritus. Opioid agonist-antagonists typically reverse these effects
without reversing analgesia.
Routes of opioid administration for postoperative pain
1. Conventional (IV / IM / SQ / PO / PR)
Probably the most common route of administering opioids is by intermittent IM
or SC injections. Since IM and SC injections of opioids have variable absorption
and are painful and time-consuming, one should use
other routes if possible. Patients with severe postoperative pain should be
administered opioids via IV PCA (see below) or epidural or intrathecal injections.
The PO route, if tolerated, would also be an option but the
likelihood of under-dosing opioids orally must be considered.
2. Patient controlled analgesia (PCA)
The rationale for PCA is the following: as-needed (prn) opioid dosing leads to
episodes or cycles of pain that in turn lead to as-needed dosing of an analgesic.
The episodes of pain that occur between analgesic doses lead to increased
anxiety. The relatively large doses of opioids used to "rescue" patients typically
are followed by periods of excessive sedation. PCA uses frequent administration
of “mini” doses of analgesics initiated by patients, thereby eliminating the peaks
and valleys of analgesia and pain. Overall, improved patient satisfaction results
from the control over analgesic medication. Typically, the total quantity of
analgesic required is smaller with PCA than conventional as-needed dosing, so
less severe and fewer adverse effects occur with PCA. Nursing time may also be
saved. Relative contraindications to PCA include the inability to use the PCA
18. button effectively because of physical or cognitive reasons, patient desire not to
assume responsibility over analgesic administration, or a history of substance
abuse. Family members and nurses typically are not permitted to activate the PCA
device. Institutions that have IV PCA capability have staff members who are
knowledgeable in the use of the
various devices available. They are also able to diagnose and are prepared to
manage potential, rare complications, including respiratory distress, apnea, and
other adverse effects typically seen with opioids. The three programmable
parameters on most PCA devices are dose, frequency and an optional continuous,
basal infusion rate. PCA is not limited to the IV route; epidural PCA, PO PCA and
SC PCA have all been used with success.
3. Neuraxial (epidural/intrathecal)
Neuraxial opioids may be administered in the epidural or intrathecal
(subarachnoid) space. Delivered at these sites, they bypass the blood-brain
barrier and require significantly lower doses, typically 1/10 to 1/100
of the effective IV dose. Epidural and intrathecal opioids are extremely effective
for the management of severe pain whether it is postoperative, chronic, or
malignant in origin. Opioids administered in the epidural space must enter the
cerebrospinal fluid (CSF) by the dura and pia mater, diffuse through the water
phase of the CSF, then cross the lipid membranes of the neuraxis to reach opioid
receptors in the substantia gelatinosa. Hydrophilic agents, such as morphine,
demonstrate increased latency and duration of action because their water
solubility retards diffusion out of the CSF and into the substance of the spinal
cord. Because of the depot of agent that remains dissolved in CSF, rostral spread
of the drug is increased. Rostral spread of drug is associated with a small risk of
delayed respiratory depression, typically 6 to 8 hours after administration.
Because hydrophilic agents remain in the CSF, uptake into the epidural blood
vessels is slow, and the administration of epidural hydrophilic opioids is
associated with low or undetectable systemic blood levels. Thus, water-soluble
opioids administered spinally exert their analgesic effect spinally. Lipid-soluble
agonists, such as fentanyl, have a rapid onset of action and provide segmental
analgesia with less rostral spread of drug. Lipid-soluble opioids also have a rapid
rate of diffusion into the venous plexus of the epidural space, resulting in rapid
drug removal from the neuraxis and achievement of therapeutic IV blood
levels. Controversy exists regarding whether epidurally administered lipid-soluble
agents, such as fentanyl and sufentanil, exert their analgesic effect primarily at
the neuraxis or by systemic absorption and hematogenous drug delivery to the
19. CNS. Neuraxial opioids can be administered by a single bolus injection into the
epidural space or CSF or by a continuous infusion via an indwelling catheter. No
change occurs in autonomic function, and light touch
sensation and proprioception are preserved. The frequency of urinary retention is
increased, mandating bladder catheterization in approximately one-third of
patients. Other possible adverse effects include nausea and vomiting, pruritus,
and acute or delayed respiratory depression.
4. Novel
Because fentanyl is extremely lipophilic, it can be readily absorbed across any
biologic membrane, including the skin. Thus, it can be given painlessly by new,
non-intravenous routes of drug administration, including the transmucosal (nose
and mouth) and transdermal routes. Transmucosal fentanyl is extremely
effective for acute pain relief. For oral-buccal administration using this novel
delivery technique, fentanyl is manufactured in a candy matrix (Fentanyl Oralet)
attached to a plastic applicator (similar to a lollipop). As the patient sucks on the
candy, fentanyl is absorbed across the buccal mucosa and is rapidly absorbed (in
10 to 20 minutes) into the systemic circulation. The major adverse effect is
nausea and vomiting, which occurs in approximately 20% to 33% of patients who
receive it. This product is available only in hospital
(and surgicenter) pharmacies and, like all sedative-analgesics, requires vigilant
patient monitoring. When drugs are administered transdermally, a patch with a
selective semipermeable membrane and reservoir of drug is applied to the skin.
The patch allows for the slow, steady absorption of drug across the
skin. The only opioid currently approved by the Food and Drug Administration
(FDA) for transdermal application is fentanyl. Transdermal fentanyl is
contraindicated for acute pain management and is used only for patients with
chronic pain (e.g., cancer) or in opioid tolerant patients. The onset of action is
16 hours after application of the patch, and fentanyl continues to be absorbed
from the subcutaneous fat for almost 24 hours after the patch is removed. These
characteristics make it hazardous to use in an acute pain setting.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33. NON STEROIDAL ANTI INFLAMMATORY DRUGS:
ACETAMINOPHEN AND NSAIDs
Acetaminophen and the NSAIDs are among the most commonly used analgesic
medications. Their efficacy has been established in certain types of postoperative
pain (cf. Cochrane reviews, acetaminophen with and without codeine, ibuprofen
and diclofenac). They are most effective in the treatment of mild to moderate
pain and are also effective as adjunctive or opioid-sparing agents in the treatment
of moderate to severe pain (NHMRC, 1999). Although these medications are
widely used and have documented efficacy for postoperative pain, they are
associated with adverse effects that should be considered when selecting
analgesic therapy.
Key points
• Acetaminophen and the NSAIDs (including COX-2–selective inhibitors) act by
mediating pyretic and pain pathways. NSAIDs (including COX-2–selective
inhibitors) also have anti-inflammatory properties.
• These agents are generally safe and well tolerated. However, excessive doses of
acetaminophen have been associated with hepatotoxicity. NSAIDS (including COX-
2–selective inhibitors) can cause significant alteration in renal, bronchial, and
gastric mucosa function.
• NSAIDs (including COX-2–selective inhibitors) should be avoided in patients who
have
34. - hypersensitivity to NSAIDs, particularly in patients who have developed NSAID-
or aspirininduced asthma, rhinitis, nasal polyps, or other symptoms of allergic or
anaphylactoid reactions;
- hypersensitivity to sulfonamides (avoid celecoxib);
- peptic ulcer disease; or
- significant renal impairment.
• NSAIDS (including COX-2–selective inhibitors) should be used with caution in
patients who
- are elderly (age > 65 years);
- have hypertension;
- have renal impairment; or
- have congestive heart failure.
• Adverse reactions occurring with NSAIDs (including COX-2–selective inhibitors)
include the
following:
- anaphylaxis
- GI bleeding
- intraoperative bleeding
- acute renal failure
- bronchospasm
- thrombocytopenia
- Stevens-Johnson syndrome
- nephritis
- hepatotoxicity
- agranulocytosis
• Common reactions experienced by patients taking NSAIDs (including COX-2–
selective inhibitors) include the following:
- stomach upset
- nausea
- abdominal pain
- constipation
- diarrhea
- headache
- dizziness
- rash
- urticaria
- drowsiness
35. - fluid retention
- tinnitus
• Decisions regarding the use of acetaminophen or an NSAID for postoperative
analgesia should be guided by the patient’s characteristics and the desired
balance between analgesic efficacy and adverse effect.
36.
37.
38. PRINCIPLES OF ANALGESIC USE:
Persistent pain requires prophylactic (preventive) Therapy:
Analgesics should be given regularly, and prophylactically. The aim is to titrate
the dose of the analgesic against the patient's pain, gradually increasing the dose
until the patient is pain-free. The next dose is given before the effect of the
previous one has fully worn off-and therefore before the patient may think it
necessary (Fig. 1 and 2). In this way it is possible to erase the memory and fear of
39. pain. If a drug ceases to be effective, do not transfer to an alternative of
comparable efficacy but prescribe a drug that is definitely stronger. If a strong
analgesic other than morphine is used, the physician must be familiar with its
pharmacology. For example, pethidine (meperidine) is effective for an average of
2-3 hr. Yet it is commonly prescribed every 4 or 6 hr. This is clearly insufficient,
and forces the patient to be in pain for perhaps 3 out of every 6 hr.
Use oral medication whenever possible:
The route of administration is a significant consideration because it has
substantial impact on the patient's way of life. The patient taking oral medication
is free to move around, travel in a car and, most important, be at home. Injections
promote dependence on the person administering the drug. Oral administration
eliminates muscle trauma, and enables the patient to maintain control over his
own drug administration.
Doses should be determined on an individual basis:
The effective analgesic dose varies considerably from patient to patient. The right
dose of an analgesic is that which gives adequate relief for at least 3 and
preferably 4 or more hours. 'Maximum' or 'recommended' doses, derived mainly
from post-operative parenteral single-dose studies, are not applicable
in cancer. The dose of morphine and other strong narcotic agonists can be
increased almost indefinitely. On the other hand, the non-narcotics, weak
narcotic agonists and narcotic agonist-antagonists all reach a plateau of maximum
effect after 2 or 3 upward dose adjustments. Thus, if the upper effective dose has
been reached with one of these agents, the dose should not be increased further
but a stronger drug should be prescribed.
Keep it simple:
The three basic analgesics are aspirin, codeine and morphine. The rest should be
considered alternatives of fashion or convenience. Appreciating this helps
prevent 'kangarooing' from analgesic to analgesic in a deperate search for some
drug that will suit the patient better. If a non-narcotic or weak narcotic
preparation, such as aspirin-codeine or paracetamoldextropropoxyphene,
fails to relieve, it is usually best to move directly to a small dose of oral morphine
sulphate than, for example, to prescribe dihydrocodeine.
It is necessary to be familiar with one or two alternatives for use in patients who
cannot tolerate the standard preparation. Aspirin has two alternatives:
40. paracetamol, which has no anti-inflammatory effect, is one: non-steroidal anti-
inflammatory drugs as a group are the other. Which alternative is appropriate
depends on whether there is need for a peripheral anti-inflammatory effect. The
individual doctor's basic analgesic ladder, with alternatives, should comprise no
more than 9 or 10 drugs in total. It is better to know and understand a few drugs
well than to have a passing acquaintance with the whole range. The following
points should be noted:
(1) With mild or moderate pain, use a non-narcotic in the first instance.
(2) It may be appropriate to prescribe aspirin in addition to a narcotic, especially
in patients with bone pain.
(3) It is logical to combine analgesics that act via different mechanisms, for
example: aspirin and paracetamol; paracetamol and codeine; aspirin and
morphine. However, it is not always wise from the point of view of patient
compliance, nor is it always therapeutically necessary.
(4) It is pharmacological nonsense to prescribe either two weak or two strong
narcotics simultaneously.
(5) There is sometimes a place for a patient on a strong narcotic to have another
narcotic (weak or strong) as a second as required analgesic for occasional
troublesome pain, though generally patients should be advised to take an extra
dose of their regular medication if 'breakthrough' pain occurs.
(6) If one weak narcotic preparation does not control the pain, do not waste time
by prescribing an alternative; move to something definitely stronger.
(7) Morphine or an alternative strong narcotic should be used when non-narcotics
and weak narcotics fail to control the pain (Table 3).
(8) 'Morphine exists to be given, not merely to be withheld.' The severity of the
pain determines the choice of analgesic, not the doctor's estimate of life
expectancy-which is often wrong. A patient should not be made to wait in pain
until the last days or hours of life.
(9) Morphine may be given in a wide range of doses from as little as 5 mg to more
than 500 mg.
(10) Do not prescribe a narcotic agonist-antagonist, such as pentazocine or
buprenorphine, with a narcotic agonist.
(11) Preferably do not prescribe pentazocine, pethidine or dextromoramide
(Palfium). The first is a weak narcotic by mouth and frequently causes
unpleasant mental effects. All three tend to be shortacting (2-3 hr).
(12) Many cancer pains respond better to the concurrent use of an analgesic and
a 'co-analgesic' Adjuvant medication is often necessary Laxatives are almost
41. always necessary, especially with patients receiving a narcotic. Unless the doctor
is fairly experienced, an antiemetic should be prescribed routinely with morphine
or other strong narcotic. If the patient is very anxious, an anxiolytic should be
prescribed. If a patient remains depressed after 1-2 weeks of much improved pain
relief, an antidepressant may be necessary, this. Do not use mixtures routinely At
some centres, for cancer pain, morphine is always prescribed with a second drug,
either cocaine (a stimulant) or a phenothiazine (a tranquillizer). Sometimes both
are added. In these circumstances,
increasing the dose of morphine can be hazardous if, by increasing the volume of
the mixture taken, the dose of the adjunctive medication is automatically
increased also, regardless of need. Depending on the adjunctive drug, this can
lead to agitation and restlessness or to somnolence. It is far better to give
adjunctive medication separately, either as a syrup or tablet/capsule. The dose of
each pharmacologically active substance can then be adjusted individually to
patient need.
Insomnia must be treated vigorously:
Discomfort is worse at night when the patient is alone with his pain and his fears.
The cumulative effect of many sleepness, pain-filled nights is a
substantial lowering of the patient's pain threshold with a concomitant increase in
pain intensity. Sometimes it is necessary to use morphine at night in patients well-
controlled during the day by a weak narcotic; or to use a considerably larger dose
of morphine at bedtime to relieve pains that are
particularly troublesome when lying down for a prolonged period.
It is sometimes necessary to balance the degree ofrelief against unwanted side
effects:
Examples include aspirin and gastric irritation, and morphine and gastric stasis.
Generally, there are two ways round these problems but occasionally a
compromise is necessary.
Admission is sometimes necessary to achieve pain control:
Particularly in a hospice, a patient is affected by far more than drug changes. He is
surrounded by a team of people who are confident that the pain will
come under control. Peer support comes from the other patients in the four or
five bed unit who relate their own stories of having achieved good pain
42. control. The patient sees the other people receiving regular medication and
observes that, except for the very ill, they are alert and functioning normally.
HOW TO CHOOSE NSAID’S IN CLINICAL SITUATIONS:
Why to choose? The question arises as to why it is necessary to choose a
particular NSAID when all have similar pharmacological profile? The answer
is that their safety, tolerability, and efficacy differ in clinical situations.
Decision of using NSAIDs in most therapeutic situation is empirical,
but certain principles can help clinicians prescribing them safely and effectively.
We review some of them.
1. Clinicians should familiarise themselves with minimal number of drugs : Most
rheumatologists feel that clinicians should familiarise themselves with a dozen of
NSAIDs and try to get full information about them. Under most circumstances,
this list should not generally exceed 20 drugs so that safe and
effective use of the drugs can be achieved.
2. Analgesia and antipyretic uses : Choosing a NSAID for its analgesic and
antipyretic effect in indications like fever, common cold, dental pain, minor soft
tissue injuries, musculoskeletal pain, and non-specific body aches is not
difficult as in most circumstances the drug is to be used for a short duration only.
Both newer drugs, e.g., celecoxib and rofecoxib have now been approved by FDA
for short-term relief of pain and inflammation.
3. Anti-inflammatory use : Choice of NSAID for chronic and disabling inflammatory
joint diseases like rheumatoid arthritis and osteoarthritis is governed by age,
diagnosis, degree of severity, relative gastrointestinal
safety, tolerability, and relative efficacy in the given clinical situation. It is a
common misconception that all NSAIDs are therapeutically equally efficacious and
any one of them could be used for the given indication. Use of multiple NSAIDs
should be discouraged. An agent with comparatively less GI side effects like
ibuprofen and diclofenac should be preferred in place of indomethacin,
piroxicam, or naproxan, which are more gastrotoxic. In situations, e.g.,
osteoarthritis where inflammation of joints is minimal analgesics, like
paracetamol should be preferred over anti-inflammatory drugs like
ibuprofen. American Rheumatological Association recommends use of 1 gm of
paracetamol every 6 hours for pain relief in osteoarthritis. In situations where
diagnosis is uncertain, the drug should be empirically chosen and given for a week
43. or so and if the response is adequate it should be continued until side effects
mandate its withdrawal. Ankylosing spondylitis, for unknown reasons,
responds better to a particular NSAID like indomethacin. It is probably related to
its stronger inhibition of prostaglandin synthesis. Under some situations, choice of
NSAIDs is very obvious. Stroke prevention, post-myocardial
infarction prophylaxis, and patient with atrial fibrillation are therapeutic
situations where aspirin is the drug of choice because of its unique antiplatelet
property of acetylating and causing irreversible inactivation of cyclooxygenase –1
isoform in the platelets. Other NSAIDs inactivate this enzyme reversibly and
therefore do not cause sustained antiplatelet effects. Aspirin has also been
adequately studied in the chemoprevention of colon cancer. Mefenamic acid is
supposed to relieve the pain of dysmenorrhoea better than other NSAIDs,
although GI side effects often limit its use.
4. Consider substitution, if there is no response with one drug : Surprisingly,
NSAIDs have large inter-patient variations, reasons of which are not entirely clear.
Even when drugs are from the same chemical family or are structurally similar,
they can be substituted. One patient may respond to one agent of one class but
may not respond to another agent of the same class. Determination of the
therapeutically effective dose for a particular patient is difficult and is
often based on ‘hit and trial’ method. Treatment should be started on low dose
and response should be awaited. If response is adequate, treatment is continued
for one week as most side effects of NSAIDs appear in the first week. In case of no
response, change of NSAIDs should be considered. Persistent dyspepsia is one of
the most frequent side effects of NSAIDs and with few exceptions it can be an
indicator of onset of future gastrointestinal (GI) toxicity. Newer agents like
celecoxib, nabumatone, and etodolac have
been shown to be almost 4-fold less GI toxic than the older ones. Studies
regarding the GI safety of nimesulide have not shown the reduced risk of
complications.
5. Avoid using multiple NSAIDS and consider ulcer prophylaxis in high-risk groups :
Some physicians consider combination of NSAIDs in the treatment of
inflammatory joint diseases. There is little evidence to support this practice
because therapeutic benefits do not add but side effects do. Moreover there is no
evidence that fixed dose combinations of NSAIDs are superior to individual drugs
in the long-term management of arthritis. Similarly, use of concomitant
gastrotoxic drugs should be avoided, e.g., corticosteroids and NSAIDs.
44. Patients at high risk may require ulcer prophylaxis and these are summarised in
table I. Ulcer prophylaxis can be started with misoprostol (PGE1) 100 microgram
daily in four divided dosages. An increasing dosage schedule results in side effects
like diarrhoea in upto 25% of patients and often limits the
dose. Omeprazole has been found to be protective in a large international study
(73 centers, 15 countries) involving 541 patients. Omeprazole (20 mg/40 mg/d)
was compared in a double-blind manner with ranitidine 150
mg twice daily2. Ulcer healing rates in patients on omeprazole were 80% and all
were taking NSAIDs concomitantly. Similarly, in another study3, omeprazole
(20/40 mg/d) was compared with misoprostol 200 microgram four times daily.
Results are summarised in table II. The common outcomes of these studies
were as follows :
a. Omeprazole was clearly superior to other agents for both prophylaxis and
treatment of NSAID-induced gastrointestinal injury.
b. H2 blockers like ranitidine have yielded disappointing healing rates.
c. Effects of omeprazole were unrelated to dose. Maximum effects seen were at
20 mg daily dose. Further increase did not lead to increase in therapeutic
benefits. Table I : Predisposing factors for NSAID induced GI ulceration.
Female gender
Advanced age (> 65)
Previous history or active peptic ulceration or ulcer
complications
Smoking, alcoholism
Heavy coffee consumption
Concomitant ingestion of GI toxic drugs (e.g., Steroids)
Prolonged use of heavy doses of NSAIDs.
For prevention of ulcers, lowest dose of NSAID should be used for short duration,
less gastrotoxic drugs like paracetamol, ibuprofen, and diclofenac should be
preferred over potent NSAIDs like indomethacin and phenylbutazone. Use of
antacids and H2- blockers like ranitidine for the prevention of NSAID-induced
ulcers should be avoided as it is not only without any benefits but may also be
harmful as they may mask early warning
symptoms of ulcer, thereby delaying the diagnosis. In their presence, ulcer may
perforate asymptomatically. Moreover, reduction of gastric acid output to
minimal leads to colonization by H. pylori – a known predisposing factor for ulcer
genesis.
45. 6. NSAID use in children : Choice of NSAIDs in children is generally restricted to
paracetamol, aspirin, naproxan, and now nimesulide. Although nimesulide has
been shown to be superior to the existing drugs in childhood febrile illnesses like
upper respiratory infections, but it is costlier than the conventional NSAIDs.
Aspirin is not recommended as a routine analgesic and
antipyretic drug in childhood viral illness because of fear of Reyes syndrome.
However, it enjoys its reputation as an anti-inflammatory agent in the
management of rheumatic fever and childhood arthropathies.
6. Topical or systemic administration?
Topical NSAIDs represent an attractive alternative to systemically administered
drugs. Studies have shown that topically applied NSAIDs directly reach to the
synovial fluid, menisci, and articular cartilages. Generally, 70-80% of the plasma
concentration reaches the articular tissues. Interestingly, in one study,
the topically applied NSAID concentrated in the menisci and cartilage to about 20-
30 folds of the systemic concentration. Although the mechanisms through which
they reach the joints remain to be exactly determined, the reported plasma
concentration is generally less then 15% of the systemic concentration.
Moreover, maximal concentration after topical administration is uniformly below
the accepted therapeutic concentration for NSAIDs, at which systemic toxicity
appears. Bioavailability studies have shown that NSAIDs administered topically
achieve only 3-5% of the systemic concentration when compared with oral
administration. This, therefore, affords major protection from life-threatening
toxicities. Topically applied NSAIDs rarely exhibit systemic side effects and most
(95%) of the side effects are dermatological in nature-like rashes and/ or pruritis.
Topical administration of NSAIDs offers advantage of local, enhanced delivery of
drugs to affected tissues with a reduced incidence of systemic effects. Empirical
clinical evidence suggests that topical NSAIDs are as effective as oral ones in the
treatment of rheumatic disease. Positive treatment outcome ranges from 30 to
95% with considerable interpatient
variability. So the question arises – should topical NSAIDs be preferred in these
situations over oral ones? The answer is difficult at the moment as their efficacy
needs to be evaluated in large placebo-controlled double blind studies before we
can actually reach this conclusion. Nevertheless, if patients cannot
tolerate the oral NSAIDs or if these are contraindicated, then topical NSAIDs are a
safe and viable therapeutic option.
46. 7. NSAIDs in pregnancy : All NSAIDs in general are to be avoided in pregnancy. If
NSAID is required, then a low dose of aspirin is probably the safest. Paracetamol is
another drug of this class that can be used for the same purpose. Aspirin should
be stopped prior to delivery to avoid complications like prolonged labour,
increased post-partum haemorrhage, and premature closure of ductus arteriosus.
Cost effectiveness of individual NSAIDs should be
considered as newer agents are considerably more expensive that conventional
ones.
FACTORS INFLUENCING CHOICE OF ANALGESICS:
The choice of the best analgesic to help manage pain from a dental emergency is
influenced by a number of factors. These include:
• Severity of the pain
Clinical judgment is required to determine the patient’s anticipated level of pain
following the management of the dental emergency. A very arbitrary and
subjective classification is: mildmoderate, moderate-severe, or severe.
• Medical history of the patient
Factors which would contraindicate non-steroidal anti-inflammatory drugs
(NSAIDs) would include gastric ulceration, bleeding concerns, severe asthma, late-
term pregnancy and significant renal disease. Avoid NSAIDs in patients taking
drugs which can interact, such as lithium, anticoagulants or antineoplastic doses
of methotrexate. NSAIDs should only be used for 4 days
or less if the patient is taking an anti-hypertensive of the classes angiotensin-
converting-enzyme inhibitors, diuretics or beta-blockers. Significant liver disease
would require a reduction in doses of any analgesic selected.
• Known allergies Allergy to ASA or any NSAID rules out use of any other NSAID. In
particular, ASAinduced asthma rules out use of any NSAID. A true allergy to
codeine contraindicates its use as well as that of oxycodone.
47. COMBINATION ANALGESIC THERAPY FOR POSTOPERATIVE DENTAL PAIN:
Analgesic monotherapy has shown equivocal success in treating dental pain. The
goal of combining analgesics with different mechanisms of action is to use lower
doses of the component drugs, thereby improving analgesia without
increasing adverse effects. This can be achieved by targeting different pain
pathways simultaneously and increasing range of action by combining
a fast-onset, short-acting analgesic (such as acetaminophen) for milder pain with
a sloweronset, longer-duration analgesic (such as codeine or tramadol) for more
severe pain. Also, when used in combination, the additive and
synergistic effects of different analgesics may allow for lower doses.
Ceiling effect. The ceiling effect helps explain why combination
therapy can be useful with acetaminophen and NSAIDs. Even
48. after administration of clinically recommended doses, some patients
will require additional analgesic therapy.92 Because of the ceiling
effect (indicated by the relatively flat part of the dose-response curve), further
increases in the dose of acetaminophen or NSAID beyond a certain point will
produce minimal increase in analgesic effect but generally will increase side
effects.93 There is a ceiling dose for analgesia with NSAIDs, and higher dosing is
required for an anti-inflammatory effect. The ceiling effect also can explain how
toxicity may occur, particularly with the use of over-thecounter acetaminophen or
NSAID preparations. Patients frequently are unaware of the risks of taking
increased doses of medication and consider only the potential benefits of
increased effectiveness. The reasoning is that if one tablet of a
drug has an inadequate effect, then taking two or more tablets should achieve a
twofold or greater response, thereby providing sufficient therapeutic
effect. But, because of the ceiling effect, the expected increased pain relief does
not occur and toxicity may result. More is not necessarily better.
Acetaminophen inadvertently may be administered concomitantly with another
preparation containing acetaminophen, so clinicians need to
educate patients about the potential risk of taking too many acetaminophen
products. Although significant side effects are rare when acetaminophen is taken
at therapeutic doses, acute toxic doses of more than 100 mg/kilograms
in adults and 150 mg/kg in children can cause hepatotoxicity. A ceiling effect may
sometimes be seen for side effects. For example, at low doses, there is a
doseresponse relationship for respiratory depression with certain opioids. But, at
higher doses, no additional respiratory depression may occur. However, the
“ceiling” for respiratory depression may be higher than the typical analgesic
doses. Traditionally, a therapeutic dose of a nonopioid has been used to
achieve maximal possible analgesia through one mechanism of action when it is
combined with the minimal dose of opioid that provides additive analgesia
without unacceptably increasing side effects. Clinical trials using combinations of
acetaminophen or an NSAID with an opioid or tramadol in dentistry have been
reported, but no studies have been published to date using a COX-2 NSAID with
an opioid or tramadol for pain related to dental procedures.
Acetaminophen combinations. Acetaminophen is an effective analgesic for mild
pain, but to manage more severe pain it typically is combined with codeine or one
of its derivatives. Opioid and acetaminophen combination
studies show that a combination is better than opioids or acetaminophen alone.
Analgesic advantages for oral surgery are optimal with acetaminophen 1,000 mg
49. combined with codeine 60 mg or a codeine derivative such as oxycodone 10 mg
with acetaminophen 1,000 mg if the pain is more severe. Acetaminophen 650 mg
plus oxycodone 10 mg has been shown to be effective compared with placebo in
managing postoperative dental pain. An acetaminophen dose as low as 500 mg
combined with oxycodone 5 mg is more efficacious in the treatment of dental
pain than is either drug alone. The combination of acetaminophen 650 mg and
codeine 30 mg was slightly more effective than acetaminophen alone as
determined by pain intensity difference and pain relief scores. Other studies have
combined acetaminophen 500 mg with hydrocodone 5 mg or acetaminophen 300
mg with codeine 30 mg and
demonstrated analgesia better or equal to placebo, but found no difference
between the two combinations for the treatment of pain related to third-molar
extraction surgery. While acetaminophen 300 mg plus codeine 30 mg was not
significantly more effective than placebo for TOTPAR and peak pain relief, overall
evaluation and total anxiety control was significantly better for the combination
drug. However, a higher dose of hydrocodone, such as 7.5 mg, combined with
acetaminophen 500 mg had slightly more analgesic efficacy than did codeine 30
mg plus acetaminophen 300 mg, and both were better than placebo for oral
surgery.104 Both treatments resulted in analgesia that began 30 minutes after
administration of the drug and continued for five hours. Since tramadol 150 mg
alone has been shown to have better efficacy overall than the combination of
propoxyphene 65 mg and acetaminophen 650 mg, as well as propoxyphene
alone,105 the combination of acetaminophen and tramadol would be expected to
provide greater analgesia than the combination of acetaminophen and
propoxyphene. In a study involving 1,197
patients with moderate-to-severe dental pain following extraction of two or more
third molars, the combination of tramadol 75 mg with acetaminophen 650 mg
provided more effective, rapid and long-acting pain relief than did tramadol or
acetaminophen alone. The estimated time to onset of action for tramadol plus
acetaminophen was 17 minutes (vs. 51 minutes for tramadol and 18 minutes for
acetaminophen) and the duration of action (time to remedication) was 5.0 hours
(vs. 2.0 hours for tramadol and 3.1 hours for acetaminophen). The tramadol and
acetaminophen combination also has demonstrated efficacy for other types of
pain, including low back pain and osteoarthritis.
NSAID combinations. Similar to acetaminophen, NSAIDs have a ceiling effect and
therefore should be combined with other analgesics for total pain relief after
major surgery. NSAIDs also allow for a significant dose reduction
50. of opioids and hence can be useful in minimizing opioid side effects. Opioids such
as codeine, hydrocodone and oxycodone typically are combined with aspirin or
ibuprofen to manage acute dental pain. The combination of ibuprofen 400 mg
and codeine 60 mg is superior to ibuprofen 400 mg alone as determined by a
metaanalysis of randomized controlled clinical studies
(including studies of dental pain). Ibuprofen 400 mg and oxycodone 10 mg
provided a faster onset of relief from dental pain than did ibuprofen 400
mg alone. The combination of ibuprofen with 2.5 or 5 mg of oxycodone was not
significantly different from ibuprofen alone in providing pain relief. The
combination of hydrocodone 15 mg combined with ibuprofen 400 mg was
superior to ibuprofen 400 mg alone for all hourly measurements of analgesia after
abdominal surgery, and side effects were associated primarily with the GI
and central nervous systems. The combination of ibuprofen 400 mg with
hydrocodone 15 mg was superior to the combination of acetaminophen 600
mg with codeine 60 mg in providing analgesia after third-molar extraction, as
demonstrated by superior total analgesic effect, duration of analgesia and global
evaluation. Tramadol has been shown to be effective at managing dental pain
when combined with a peripherally acting NSAID. Combining tramadol 100 mg
with the NSAID flurbiprofen (100 mg) significantly reduced pain vs. placebo at six
hours and 24 hours following pulpectomy (a weak analgesic model); neither
tramadol nor flurbiprofen significantly relieved pain vs. placebo at six and 24
hours when used as monotherapy. This is an
important therapeutic finding for the management of endodontic pain, since
NSAIDs have a ceiling dose and some patients may require analgesia
beyond the recommended dose. Tramadol and diclofenac have been shown to be
effective in pain management by some researchers, while no added effect was
found by others. Tramadol plus ibuprofen increased the efficacy of pain relief in
patients with various types of dental pain. Importantly, tramadol has been shown
in clinical trials to allow for dose-sparing with ibuprofen and naproxen.
ADJUVANT ANALGESICS(CO-ANALGESICS):
These drugs are not analgesics actually in pharmacological sense but may
contribute significantly to pain relief when used alone or in combination with
other analgesics.
Drugs which act as adjuvants are
Anti depressants
Anti convulsants
51. Cannabinoids
Bisphosphonates
Alpha adrenergic agonists
Tricyclic antidepressants: These drugs are used as primary analgesics for decades.
They provide analgesia for different kinds of pain but not for all. These provide
analgesia for pain from nerve damage, fibromyalgia, headache and migraine.
Mechanism of action: Actual mechanism of action is not clear but it may increase
neurotransmitters in the spinalcord that reduce pain signals or may act through
histamine receptors or modulation of sodium channels.
Anticonvulsants: These act by suppressing the spontaneous neuronal discharges
and neuronal hyperexcitability that occur after nerve injury. Eg gabapentin,
carbamazepine.
Antiepileptics like phenytoin, valproic acid also has anti hyperalgesic and anti
nociceptive effects.
Alpha2 adrenergic agonists: These show spinal anti nociceptive effect via alpha2
receptor subtypes. These induce analgesia by acting at 3 sites brain, spinalcord
and peripheral tissues.