Pain management vels


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  • Ref from Julie:
    Ferris F, Balfour H, Bowen K, Farley J, Hardwick M, Lamontagne C, Lundy M, Syme A, West P. A model to guide patient and family care. Based on nationally accepted principles and norms of practice. J Pain Symptom Manage. 2002;24(2):106-23. PMID: 12231127 and Ferris FD, Balfour HM, Bowen K, Farley J, Hardwick M, Lamontagne C, Lundy M, Syme A, West P. A model to guide hospice palliative care. Ottawa, ON: Canadian Hospice Palliative Care Association, March 2002. Available at
  • Answer: 4
  • Showing pain sensors in the skin
    Otherwise called NOCICEPTOR
  • Reference: Polomano, R.C. (2010). Neurophysiology of Pain. In B. St. Marie (Ed.) Core Curriculum for Pain Management Nursing. Lenexa, KA: American Society for Pain Management Nursing, p. 68.
  • Surgical operations produce local tissue damage with consequent release of algogenic substances and of a barrage of noxious stimuli, which are transduced by nociceptors into impulses that are transmitted to the neuraxis by A-delta and C fibers.
    Cortical responses occur in the awake patient. They are provoked by nociceptive impulses that reach the highest parts of the brain, in which they activate complex systems concerned with recognition of the sensation of pain.
    When the effects of surgical anaesthesia disappear, the patient’s injury persists and algogenic substances continue to be liberated and sensitise nociceptors.
    Such pathophysiologic changes are greatly enhanced by sympathetic hyperactivity and by the consequent liberation of noradrenalin, which sensitises nociceptors and damaged nerve membrane.1
    These processes are partially balanced by the descending control system, which inhibits the recapture of serotonin and noradrenalin at spinal level and generates endorphins that block the opioid receptors.
  • The causes of acute pain are often known, but the causes of chronic pain and its associated symptoms are not well understood.1
    The pain experienced by patients with acute pain often can be alleviated. In general, the duration of acute pain is brief and has been well characterized.1 The time course of chronic pain, however, is usually indeterminate, and patients with chronic pain are often refractory to treatment.2
    One definition of chronic pain is pain that has persisted beyond the time of normal healing; for research purposes, however, chronic pain is often defined as pain that has persisted at least 3 (sometimes 6) months.3
    Because chronic pain can almost never be cured,4 optimal treatment usually involves helping the patient restore function and supporting a patient’s coping by utilizing approaches that minimize pain, maximize QOL, improve sleep, and enable patients to return to work and perform their regular activities.3,4
    1.Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, Minn: The McGraw-Hill Companies, Inc; 2000:7-8.
    2.Rowbotham MC. Chronic pain: from theory to practical management. Neurology. 1995;45(suppl 9):S5-S10.
    3.Portenoy RK, Kanner RM. Definition and assessment of pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Company. 1996:6.
    4.Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet. 1999;353:1959-1964.
  • At least 4 distinct types of pain exist: nociceptive, inflammatory, neuropathic, and functional. Nociceptive pain is a response to noxious peripheral stimuli, such as burning or a surgical incision. The nociceptive pain system serves as a warning system for the body to avoid potentially dangerous stimuli. It should not be “turned off” except in rare circumstances, such as surgery or dental work. Without nociceptive pain, the body is constantly at risk for injury.
    Inflammatory pain is a response to tissue damage and inflammation, such as occurs in arthritis or near an infection. It also has a protective function, in that it surrounds and protects injured tissue and helps the healing process by preventing overuse of the injured part. As anyone who has banged a toe can testify, inflammatory pain decreases as the damage resolves. However, we also have degenerative diseases, such as osteoarthritis, that continue to create inflammatory pain because the tissue damage is ongoing.
    Neuropathic pain results from damage or lesions to the nervous system - such as occur in diabetic peripheral neuropathy or postherpetic neuralgia. It tends to be burning or stabbing in nature and is not responsive to traditional pain agents such as NSAIDs or aspirin. Neuropathic pain can also result from damage to the CNS, such as in patients with MS or spinal cord injury.
    Functional pain results from a dysfunction in the central processing of pain in the dorsal horn or other regions of the spinal cord. With functional pain, no neurologic deficits or peripheral abnormalities can be detected. Examples of functional pain include fibromyalgia, irritable bowel syndrome, and some forms of noncardiac chest pain.
    Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140:441-451.
  • Nociceptive, or inflammatory, pain is pain resulting from activity in neural pathways caused by potentially tissue-damaging stimuli.1 Examples include postoperative pain, arthritis, mechanical low back pain, sickle cell crisis, and sports or exercise injuries.
    Neuropathic pain is pain caused by a primary lesion or dysfunction in the peripheral and/or central nervous systems.2 Examples of peripheral neuropathic pain syndromes include HIV sensory neuropathy, postherpetic neuralgia (PHN), and diabetic neuropathy. Examples of central neuropathic pain include central poststroke pain, spinal cord injury pain, trigeminal neuralgia, and multiple sclerosis pain.
    As indicated by the “mixed type” area on the slide, chronic pain can be of mixed etiology with both nociceptive and neuropathic characteristics.
    Two types of neuropathic pain—PHN and diabetic neuropathy—will be emphasized within this module. These types of pain are being stressed because the great majority of randomized controlled trials of treatments for neuropathic pain have examined these two disorders, and because our understanding of the mechanisms of neuropathic pain is largely derived from those studies.
    1.Portenoy RK, Kanner RM. Definition and Assessment of Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Company; 1996:4.
    2.Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, Minn: The McGraw-Hill Companies Inc; 2000:8-9.
  • A variety of terms are used to describe neuropathic pain, including those listed on the slide: burning, paroxysmal, paresthetic, lancinating, raw skin, shooting, electriclike, deep, dull, and bonelike aching pain.
    Additional terms that are often used to describe neuropathic pain include squeezing, jabbing, broken-glass, cramping, spasms, icy cold, and frostbite.
    These terms are not perfectly sensitive or specific and are to be used only as a guide: some patients with neuropathic pain will not use these terms to describe their pain experience, and some patients who use these terms have nonneuropathic pain.
    Terms used to describe pain are usually not helpful in differentiating among neuropathic conditions.1
    The cardinal signs and symptoms of neuropathic pain are allodynia and hyperalgesia, both of which are defined on the slide.2
    1.Galer BS. Neuropathic pain of peripheral origin: advances in pharmacologic treatment. Neurology. 1995;45(suppl 9):S17-S25.
    2.Backonja M-M, Galer BS. Pain assessment and evaluation of patients who have neuropathic pain. Neurol Clin. 1998;16:775-789.
  • Many mechanisms have been proposed for neuropathic pain, but it is unknown which mechanisms are most relevant in humans. This slide lists the more widely accepted proposed mechanisms. In an individual patient, more than one mechanism is probably relevant. The ability to classify patients based on predominant pathophysiology may, hopefully, help target therapy.1
    Excitotoxicity: nerve damage results in a barrage of nociceptive input released into the spinal cord that can damage inhibitory cells and result in a disinhibited pain system.2
    Sodium channels: in damaged nerves, abnormal sodium channels may be produced that result in a hyperexcitable nerve.3
    Ectopic discharge: damaged nerves produce ectopic, or abnormal, nerve impulses that may promote pain perceptions.3
    Deafferentation: if the central nervous system (CNS) is deprived of normal nerve input, as in the case of amputation or plexus avulsion, pain may result. The classic picture is severe pain in an insensate (or absent) limb.4
    Central sensitization: with repeated sensory input, the CNS may become hyperresponsive (sensitized) to peripheral input, a so-called facilitated state. This state is caused by long-term or permanent changes in the anatomy or physiology of the CNS produced by pain.1-3
    1.Galer BS. Neuropathic pain of peripheral origin: advances in pharmacologic treatment. Neurology. 1995;45(suppl 9):S17-S25.
    2. Brookoff D. Chronic pain: 1. A new disease? Hosp Pract. July, 2000:45-59.
    3. Baron R. Peripheral neuropathic pain: from mechanisms to symptoms. Clin J Pain. 2000;16:S12-S20.
    4. Portenoy RK. Neuropathic pain. In: Portenoy RK, Kanner RM, eds: Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Company; 1996:94,97.
  • The upper figure illustrates how damage to a peripheral nerve (the starburst) causes “algesic substances” to be released from the peripheral nerve terminal. The algesic substances may induce action potentials in the surrounding, intact neurons.
    Nerve injury may mediate dedifferentation of Schwann cells, causing the loss of the axon-insulation and myelin-production capabilities of these cells.
    The lower figure shows how, after this damage, the nerve may become hyperresponsive to noxious or nonnoxious stimulation, facilitating pain.
    Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and
    management. Lancet. 1999;353:1959-1964.
  • The upper portion of the slide illustrates normal function of an A nerve fiber and its dorsal horn connection. An innocuous brush-evoked stimulus activates the fiber’s mechanoreceptor, but the stimulus is not adequate to activate the dorsal horn pain pathway across a weak synapse.
    The lower portion of the slide illustrates central sensitization, by increased nociceptor drive, of the dorsal horn neuron (represented by the starburst). The A fiber input is now sufficient to activate spinal cord pain pathways.
    Central sensitization may result from:
    an effective increase in the area of the periphery eligible to activate neurons.
    an exaggerated response to a stimulus that meets the activation threshold.
    a stimulus that had been too weak to satisfy the activation threshold becomes an irritating stimulus.
    Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and
    management. Lancet. 1999;353:1959-1964.
  • Instructions to presenter: The first thing to understand about this animation is that all roads lead back to the initial screen. It can be used to point out that all of these processes have a common pathway through the NMDA receptor and go no further. All animations have stop action and further buttons that lead to next steps. To make the animation live, click anywhere on the screen. Move the cursor over a button and a pointing finger will appear and the button will change color. Lecture notes for the following buttons do not appear since they are not pertinent to this presentation: Affective Disorder, Sympathetic, Opioid Tolerance.
    NMDA RECEPTOR BUTTON: This (click) leads to the balance between glutamate and GABA in the CNS, with GABA being synthesized from glutamate via GAD. (click) Glutamate goes out of balance with GABA due to excitation in chronic pain states or chronic affective disorder. (click) The presynaptic primary afferent terminal synapses with a second order dorsal horn neuron. The red dots in the synapse are glutamate; the “P” is Substance-P. (click) Nonpain transmitting AMPA receptors receive glutamate and pass a nonpain-producing stimulus. (click) Next substance P attaches to NK-1 receptors. The postsynaptic cell transmits a signal interpreted by the brain as pain. (click) Shown here is release of Mg from the NMDA receptor and attachment of glutamate to internal sites on the receptor. (click) Ca comes in through the depolarized NMDA receptors. (click) And this shows what the process causes.
    Neuropathic Button: First we see the C and A-Beta fibers in the dorsal horn. (click) Next, damage to the nerve before the DRG. (click) Here we see the ingrowth of A-Beta fibers following nerve injury to pain signal transmitting superficial lamina of the dorsal horn, resulting in the clinical manifestation of allodynia. (click) Here is a similar molecular view as the previous slide, resulting in wind-up.
    Nociceptive Button: Here we see a process of inflammation changing from acute to chronic and then focusing down to the microscopic and molecular level of wind-up. (click) Next, a posterior view of a lumbar motion segment with Z-joints (facet joints). (click) The joint becomes inflamed. (click) Here is a microscopic look into the zone of inflammation and the release of inflammatory chemicals activating the nociceptors. (click) The nociceptors release Substance-P, ATP and calcitonin gene related peptide activating nonnociceptors to result in the transmission of signals that produce a perception of pain. (click) This all connects to the CNS and produces wind-up. (click) This shows the molecular view of wind-up pain. Initially a nonpain-producing signal causes the release of glutamate to non-NMDA receptors and no pain. (click) Pushing the button causes the release of substance-P and the amplification of the depolarization resulting in a signal interpreted as pain. (click) Here, NMDA receptors blocked by magnesium and with the pairing of Substance-P and glutamate over time, and the release of the block (click) . (click) Glutamate attaches and shows wind-up on the postsynaptic action potential.
  • Addressing analgesia, the first of the “Four A’s of Pain,” requires an assessment of pain intensity to determine whether existing treatment is providing adequate relief. This slide depicts four of the pain scales that are used to assess a patient’s pain. The scales are considered simple for patients to use as well as being validated methods for measuring the severity of pain.1-3 These scales can be used at the patient’s bedside, and patients can be asked to respond to either a spoken or written a question. The 0-10 numeric scale can be administered over the phone.
    With some scales, especially the visual analog scale, the patient marks the line at the point that best indicates the pain’s intensity. Older patients may have difficulty using visual analog scales and it might be more appropriate to use a 0-10 numeric pain intensity scale.4
    The Wong-Baker FACES Pain Rating Scale is validated and recommended for patients aged 3 years or older. On this scale, Face 0 indicates no pain at all, Face 1 feels mild pain, Face 2 feels moderate pain, Face 3 feels severe pain, Face 4 feels very severe pain, and Face 5 feels the worst possible pain. The original appears above, and can be used as is or with the brief word descriptions under each number. In a study of 148 children aged 4 to 5 years, there were no differences in pain scores when children used the original or brief word instructions.2
    People with cognitive impairments and limited ability to communicate (eg, stroke patients) may have difficulty with the use of any self-report pain assessment scales. For these patients it will be necessary for the physician to rely on behavioral observation of patients' facial expressions, movement patterns (eg, bracing, guarding, distorted postures, avoidance of activity), and nonverbal sounds (eg, moans, winces) and reports of significant others (eg, partner, spouse, child) to make judgment of pain intensity.5
    However, remember that patient pain is multidimensional and involves more than just assessment of pain intensity.
    1.Portenoy RK, Kanner RM. Definition and Assessment of Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Company; 1996:8-10.
    2. Wong DL. Waley and Wong’s Essentials of Pediatric Nursing. 5th ed. St. Louis, Missouri: Mosby, Inc.; 1997:1215-1216.
    3. McCaffery M, Pasero C. Pain: Clinical Manual. St. Louis, Missouri: Mosby, Inc.;1999:16.
    4. Jensen MP, Karoly P, Braver S. The measurement of Clinical pain intensity: a comparison of six methods. Pain. 1986;27:117-126.
    5. Hadjistavropoulos T, von Baeyer C, Craig KD. Pain assessment in persons with limited ability to communicate. In: Turk DC, Melzack R, eds. Handbook of Pain Assessment. 2nd ed. New York, New York: Guilford; 2001:134-152.
  • The “Four A’s” of outcome assessment provide a useful approach for the physician to think about appropriate follow-up for guiding optimal pain management.
    Although each of these four aspects will be discussed in detail in the following section, the key points include the importance of monitoring patients’ pain intensity to ensure that they are receiving effective analgesia (pain relief), measuring effects on activities of daily living to document improvements in patient functioning (physical, psychosocial functioning), closely monitoring for adverse effects (side effects) in order to minimize or counter these effects, and being vigilant for any signs of aberrant drug taking that may precede addiction or addiction-related behaviors.
    Most aberrant behaviors are not caused by addiction; clinical judgment is needed to differentiate these behaviors.
    Because pure mu-opioids do not possess a ceiling effect, the dose should be titrated until the patient experiences adequate pain relief or intolerable side effects. It is important to be aware that as the dose is escalated, the potential for side effects increases correspondingly. Therefore, the goal should be to optimize the therapeutic ratio.
    Passik SD, Weinreb HJ. Managing chronic nonmalignant pain: overcoming obstacles to the use of opioids. Adv Ther. 2000;17:70-83.
  • Successful opioid therapy requires periodic review of patient status and achievement of therapeutic goals. While frequency of such assessments may vary from patient to patient based on case-specific characteristics (eg, severity of pain, difficulty of titration), it is important to keep track of how the patient is faring. Measuring the success of a pain management program should parallel the ways outcomes are measured in other chronic disease states (eg, diabetes). Although a reduction in pain scale numbers is important, it should also trigger critical thinking about impact of therapy on important functional outcomes.
    If during follow-up assessment it becomes clear that a particular opioid is not providing appropriate pain relief, a different opioid should be tried, keeping in mind that dosage conversion tables found in treatment guidelines should be used with care (they provide a guide, not an absolute). If this strategy is unsuccessful, the physician may need to determine if the patient needs to be referred to a pain specialist.
    Opioid rotation may be helpful in reducing side effects that may have developed with use of the opioid a patient is currently taking.
    It is important to assess the impact of opioid therapy on activities of daily living. Has the patient been able to return to work; is the patient comfortable at work? Is the therapy controlling pain, but making it more difficult to concentrate? Has the patient’s socialization improved? If not, why not?
    Aberrant drug-taking behavior, if any, needs to be discussed and investigated. Is it a sign of addiction, or of inadequate pain management?
    A review of treatment options should periodically be undertaken. Well-controlled pain may provide an opportunity to titrate downward. Inadequate pain control may suggest the need for a polypharmaceutical approach, especially if the pain is complex, with multiple underlying mechanisms.
  • Opioids provide analgesia by mimicking the effect of endogenous opioids at specific receptors in the central nervous system.1
    NSAIDs block production of prostaglandins that sensitise peripheral nociceptors after tissue injury.1
    Paracetamol is a centrally-acting drug that selectively inhibits nervous system cyclo-oxygenase, thus inhibiting prostaglandin synthesis.2 Other central mechanisms dependent on the spinal serotoninergic pathway could also be involved.2,3
    Moreover, a recent study demonstrated that paracetamol was a potent inhibitor of a NSAID-induced cyclo-oxygenase which could be a third COX (COX-3).4
  • How do the COX-Inhibitors work? Impairs the arachidonic acid cascade.
    Tissue trauma sets off a cascade leading to the development of algesic substances that activate and sensitive peripheral nociceptors leading to the influx of acute pain signals to the CNS.
    Fortunately, the cyclooxygenase pathways involved with pain both peripherally and centrally are the COX-2 and COX-3(acetaminophen). The peripheral inflammatory COX pathways are chiefly COX-2.
  • The tricyclic antidepressants have been found to be effective for treating a variety of pain states. These agents block the reuptake of both norepinephrine and serotonin and appear to have a variety of analgesic properties that extend beyond their modulation of serotonin and norepinephrine. Newer antidepressants—the selective serotonin reuptake inhibitors—do not have analgesic properties.
    They are used to treat headaches (including migraines), low back pain, fibromyalgia, painful diabetic neuropathy, postherpetic neuralgia, central pain, and cancer pain. These antidepressants appear to be most effective for treating burning pain or hypersensitivity, but also may be beneficial for lancinating neuropathic pain.
    Their use is limited by a greater incidence of adverse events. Class effects include sedation, orthostatic hypotension, and anticholinergic effects.
    Cohen SP, Mullings R, Abdi S, Warltier DC. The pharmacologic treatment of muscle pain. Anesthesiology. 2004;101:495–526.
    Macres S, Richeimer S, Duran P. Adjuvant analgesics. In: Warfield CA, Bajwa ZH, eds. Principles & Practice of Pain Medicine. 2nd ed. New York, NY: McGraw-Hill; 2004:627–38.
    National Pharmaceutical Council, Inc. Pain: Current Understanding of Assessment, Management, and Treatments. Reston, VA: National Pharmaceutical Council, Inc; 2001. Available at: Accessed September 8, 2004.
  • Antiepileptic drugs (AEDs) have been found effective for treating a variety of neuropathic pain states. They are often recommended for treating lancinating pain—pain characterized by the patient as “shooting” or “stabbing.”
    Carbamazepine, phenytoin, gabapentin, and lamotrigine have been evaluated for their effects on neuropathic pain in randomized, controlled clinical trials.
    The AEDs have somewhat different mechanisms of action; therefore, failure to respond to one agent does not necessarily predict a poor response to other AEDs. These medications do not have a ceiling dose; rather, dosages are limited by the incidence of adverse events. Dosages should be titrated upward until adverse events appear, and then reduced to the dosage at which adverse events did not occur.
    Adverse events vary among the agents.
    National Pharmaceutical Council, Inc. Pain: Current Understanding of Assessment, Management, and Treatments. Reston, VA: National Pharmaceutical Council, Inc; 2001. Available at: Accessed September 8, 2004.
    Strasser F, Driver LC, Burton AW. Update on adjuvant medications for chronic nonmalignant pain. Pain Practice. 2003;3:282–97.
  • Anticonvulsant medications have been used in the treatment of neuropathic pain for many years without FDA approval (except for carbamazepine’s indication for trigeminal neuralgia). The slide provides a summary of many of the controlled trials that have been conducted examining the efficacy of anticonvulsant drugs in the treatment of various neuropathic pain syndromes.1,2-7
    The studies of carbamazepine and phenytoin conducted in the 1960s and 1970s do not meet today’s standards of methodological rigor.8 The phenytoin studies have produced both successful and unsuccessful results.9
    The two studies of gabapentin are among the largest clinical trials of the treatment of neuropathic pain ever conducted.8,10 These studies have stimulated a great deal of clinical and research interest in the efficacy and mechanisms of action of anticonvulsant drugs in treating patients with neuropathic pain.
    First-generation anticonvulsant drugs, which include carbamazepine and phenytoin, sometimes provoke serious side effects and drug-drug interactions that do not occur with second-generation anticonvulsants.11 We will be focusing on gabapentin because it is the anticonvulsive most commonly used for neuropathic pain and for which there is the most clinical data.
    1. Rowbotham M et al. JAMA. 1998;280:1837-1842; 2. Eisenberg E et al. Neurology. 2001;57:505-509; 3. Simpson DM et al. Neurology. 2000;54:2115-2119; 4.Campbell FG et al. J Neurol Neurosurg Psychiatry. 1966;29: 265-267; 5. Zakrzewska JM et al. Pain. 1997;73:223-230;6. Zakrzewska JM et al. J Neurol, Neurosurg, Psychiatry. 1989;52:472-476; 7. Vestergaard K et al. Neurology. 2001;56:184-190; 8. Rull J et al. Diabetologia. 1969;5:215-218; 9. Chadda VS et al.J Assoc Physicians India. 1978;26:403-406; 10. Backonja M et al. JAMA. 1998;280:1831-1836;11. Ross EL. Neurology. 2000;55:S41-S46.
  • [discuss advances in our understanding of the mu, delta and kappa opioid receptor mechanisms]
    [introduce interest over the last decade in the role of NMDA receptor in neural mechanisms of persistent pain
    NMDA-R Antagonists: Issues
    Extensive preclinical research documents involvement of the NMDA-R in:
    Central sensitization
    Neuropathic pain
    Development of analgesic tolerance
    Clinical study results of singe entity NMDA-R antagonists:
    NMDA-R antagonists alone are unlikely to act as analgesics
    Potential side effects limit clinical utility
    Rational for NMDA-R/opioid combinations]
    [but highlight challenges in translating basic research on pain to application in clinical pain management]
    [introduce idea of interactions between NMDA and opioid systems]
    Mao J. Translational pain research: Bridging the gap between basic and clinical research. Pain 2002;97:183-187.
  • Oral dextromethorphan (DM),an antitussive, is a noncompetitive antagonist of the NMDA receptor. In RCTs, dextromethorphan was superior to memantine and lorazepam at reducing pain intensity in patients with diabetic neuropathy or postherpetic neuralgia.1 Combinations of morphine and dextromethorphan have been studied for the treatment of moderate-to-severe chronic pain.1
    Ketamine belongs to dissociative anaesthetics class of drugs. A recent RCT in which ketamine efficacy was measured in patients with neuropathic pain found that ain reduction was significantly correlated with ketamine-induced changes in hallucinatory behavior and excitement.2
    Methadone is a synthetic opioid analgesic with a long duration of action, used primarily to treat pain and to detoxify or maintain patients who are addicted to narcotic pain relievers. The d-enantiomer (but not the l-)of the opioid methadone has a low micromolar affinity to the NMDA receptor. Previous in vitro and in vivo studies have determined that the d-enantiomer has NMDA receptor antagonist activity.3
    Memantine (Amantadine), an Alzheimer’s and vascular dementia therapy currently in Pharse III trials, is an uncompetitive NMDA receptor antagonist. A regulatory filing for neuropathic pain was expected in 2003.4
    Amitriptyline and other tricyclic antidepressants exhibit high affinity binding to NMDA receptors in vitro.5
    Thiopental, an ultra–short-acting barbiturate, has been shown to reduce significantly NMDA-mediated increases in intracellular calcium in vitro.6
    Meperidine hydrochloride/ Pethidine hydrochloride (Demerol) is a narcotic analgesic. Large concentrations of meperidine have been shown to inhibit NMDA receptor channels by channel block mechanisms.7
    1.Sang CN, Booher S, Gilron I, et al. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology 2002;96:1053-1061.
    2. Oga K, Kojima T, Matsuura M, et al. Effects of low-dose ketamine on neuropathic pain: An electroencephalogram-electrooculogram/behavioral study.Psychiatry Clin Neurosci 2002;56:355-363.
    3. Davis AM, Inturrisi CE. d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia. J Pharmacol Exp Ther 1999;289:1048-1053.
    4. Kilpatrick GJ, Tilbrook GS. Memantine. Merz. Curr Opin Investig Drugs 2002;3:798-806.
    5. Eisenach JC, Gebhart GF. Intrathecal amitriptyline acts as an N-methyl-D-aspartate receptor antagonist in the presence of inflammatory hyperalgesia in rats. Anesthesiology 1995;83:1046-1054.
    6. Zhan RZ, Qi S, Wu C, et al. Intravenous anesthetics differentially reduce neurotransmission damage caused by oxygen-glucose deprivation in rat hippocampal slices in correlation with N-methyl-D-aspartate receptor inhibition. Crit Care Med 2001;29:808-813.
    7. Yamakura T, Sakimura K, Shimoji K. N-methyl-D-aspartate receptor channel block by meperidine is dependent on extracellular pH. Anesth Analg 2000;90:928-932
  • For many years, anecdotal reports and small, uncontrolled studies have suggested that topical preparations with aspirin may have an analgesic effect in some patients with neuropathic pain.1 In one study, aspirin dissolved in chloroform reduced pain in 42 patients with PHN and herpes zoster.2
    The results of controlled trials of topical capsaicin in the treatment of neuropathic pain, including PHN and painful diabetic neuropathy, have been equivocal.3-5 These results are partially caused by the difficulty of conducting a double-blind trial of capsaicin because of the associated burning it causes. This problem also limited the value of capsaicin in the clinic, because few patients can tolerate repeated applications.3 Capsaicin is available in a number of over-the-counter formulations, including Zostrix, Capsin, Capzasin-P, Dolorac, R Gel, Pain-X, No Pain-HP.
    EMLA is a eutectic mixture of the local anesthetics lidocaine and prilocaine. Clinical trial results have been mixed. In one study, repeated applications of EMLA had a variable effect on pain.6 EMLA Anesthetic Disc® and EMLA Cream® are available but have not been approved by the FDA for treating neuropathic pain disorders.
    The topical lidocaine patch 5% (Lidoderm®) has been approved by the FDA for treating postherpetic neuralgia on the basis of three well-controlled trials.7-10 The effectiveness of this treatment in patients with other neuropathic pain syndromes is currently being studied; one published, open-label trial of 16 patients with refractory neuropathic pain demonstrated clinically meaningful pain relief.11
    1. Kost RG et al. N Engl J Med. 1996;335:32-42; 2. King RB. Arch Neurol. 1993;50:1046-1053; 3. Robbins W. Clin J Pain. 2000;16:S86-S89; 4. Low PA et al. Pain. 1995;62:163-168; 5. Scheffler NM et al. J Am Podiatr Med Assoc. 1991;81:288-293; 6. Attal N et al. Pain. 1999;81:203-209; 7. Lidoderm Patch (Endo Labs). Physicians Desk Reference on the internet; 8. Rowbotham MC et al. Ann Neurol. 1995;37: 246-253; 9. Rowbotham MC et al. Pain. 1996;65:39-44; 10. Galer BS et al. Pain. 1999;80:533-538; 11. Devers AD et al. Clin J Pain. 2000;16:205-208.
  • Medicine has now entered the new millennium, an era of “balance,” in which numerous government and healthcare organizations have issued guidelines supporting the appropriate use of opioids for chronic pain.
    There is a growing recognition that opioid analgesics are essential treatment options for chronic pain, yet they do have serious risk potential, and these risks can be managed.
    The goal of physicians, then, is to maximize symptom relief and functional improvement while minimizing the risks and occurrence of addiction, diversion, and other complications.
    Drug Enforcement Administration (DEA):
    US Food and Drug Administration (FDA):
    Federation of State Medical Boards (FSMB):
    American Pain Society (APS):
    American Association of Pain Medicine (AAPM):
    American Society of Pain Management (AAPM):
    American Society of Addiction Medicine (ASAM):
    American College of Radiology (ACR):
    American Geriatrics Society (AGS):
  • These strategies have been suggested by the National Pharmaceutical Council as ways to help minimize adverse effects.
    National Pharmaceutical Council, Inc. Pain: Current Understanding of Assessment, Management, and Treatments. Reston, VA: National Pharmaceutical Council, Inc; 2001. Available at: Accessed September 8, 2004.
  • Although there are common misperceptions that opioids are effective only for certain types of pain, or should be used only in the short term (for acute pain) or for cancer pain, the reality is that in the absence of effective alternatives, opioids are an indispensable tool for treating a wide range of pain types.1-4
    In addition to short-term use, opioids can be safely used long term (for cancer or chronic, persistent noncancer pain) either as needed for episodic pain or regularly for continuous pain, with appropriate monitoring, attention to management of side effects, and careful selection of agent and dosing schedule.
    Opioid analgesics may be used to treat both nociceptive pain as well as pain of neuropathic origin.5
    Dellemijn PL. Opioids in non-cancer pain: a life-time sentence? Eur J Pain. 2001;5:333-339.
    Schofferman J. Long-term opioid analgesic therapy for severe refractory lumbar spine pain. Clin J Pain. 1999;15:136-140.
    Rowbotham MC, Reisner-Keller LA, Fields HL. Both intravenous lidocaine and morphine reduce the pain of postherpetic neuralgia. Neurology. 1991;41:1024-1028.
    Lipman AG. Treatment of chronic pain in osteoarthritis: do opioids have a clinical role? Curr Rheumatol Rep. 2001;3:513-519.
    Portenoy RK. Opioid analgesics. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Company; 1996:248-276.
  • Short-acting opioids are appropriate for treatment of acute pain or breakthrough/incident pain, whereas long-acting formulations are used for patients with continuous chronic pain. Short-acting agents provide effective analgesia for acute pain but should be avoided as primary analgesics for chronic pain management. Short-acting opioids may be used during the initial dose titration period of long-acting formulations and as rescue medication for episodes of breakthrough/incidence pain.1,2
    Some short- and long-acting opioids may also contain other analgesics (eg, oxycodone/acetaminophen, hydrocodone/ibuprofen).
    1. American Geriatric Society. Clinical Practice Guidelines. The Management of Chronic Pain in Older Persons. J Am Geriatr Soc. 1998;46:635-651.
    2. McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther. 2001;8:181-186.
  • Morphine is primarily metabolized to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M3G can produce hyperalgesia, allodynia, and hyperactivity and appears to antagonize the analgesia provided by morphine. On the other hand, M6G has greater analgesic potency than morphine and produces fewer adverse events. Elevated concentrations of M3G, or an increased ratio of M3G to M6G, can produce allodynia, hyperalgesia, and myoclonus (sudden, involuntary jerking of a muscle or group of muscles) in a dose-related manner. If these effects occur, switching to another opioid may be warranted.
    Jackson KC, Lipman AG. Opioid analgesics. In: Lipman AG, ed. Pain Management for Primary Care Clinicians. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2004:59–70.
    Lugo RA, Kern SE. Pharmacokinetics of opioids in the management of pain. In: Lipman AG, ed. Pain Management for Primary Care Clinicians. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2004:71–90.
  • Propoxyphene also has an increased risk for inducing seizures compared with other opioids. This drawback, combined with the fact that it has not been proven to be more effective than acetaminophen, aspirin, or codeine, limits its use. In addition, propoxyphene can cause cardiac conduction abnormalities. Both propoxyphene and its metabolite norpropoxyphene contribute to the cardiotoxicity, whereas the neurotoxicity results solely from the propoxyphene. Naloxone does not reverse the cardiotoxicity associated with propoxyphene. Propoxyphene should be avoided in elderly patients.
    It has recently been withdrawn from the national formulary in the United Kingdom.
    FDA says it will take several weeks to decide how to proceed
    Kleinschmidt KC, Wainscott M, Ford MD. Opioids. In: Ford MD, Delaney KA, Ling LJ, Erickson T, eds. Clinical Toxicology. Philadelphia, PA: WB Saunders; 2001:627–40.
  • Subutex is just buprenorphine. Suboxone also contains naloxone to block the opioid effects if patients try to inject it.
  • Tramadol is a weak opioid agonist that is effective for treating moderate to moderately severe pain. It also inhibits reuptake of serotonin and norepinephrine.
    The most common adverse events associated with tramadol are dizziness, nausea, constipation, and somnolence, and these events are not fully reversible with naloxone. Compared with other opioids, tramadol carries a reduced risk of respiratory depression with overdosage and a low risk of physical dependence and abuse, and it is a federally nonscheduled opioid analgesic.
    American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 5th ed. Glenview, IL: American Pain Society; 2003.
    Cicero TJ, Adams EH, Geller A, et al. A postmarketing surveillance program to monitor Ultram® (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend. 1999;57:7–22.
    Moreland LW, St. Clair EW. The use of analgesics in the management of pain in rheumatic diseases. Rheum Dis Clin North Am. 1999;25:153–9.
    Ultram® (tramadol hydrochloride) [package insert]. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc; 1998 November.
  • Long-acting opioids have greater utility than short-acting opioids in treating chronic pain in patients with consistent pain levels. Long-acting, controlled-release, oral formulations of opioids (eg, morphine, oxycodone), which have a predictable duration of action lasting from 8 to 12 hours, make around-the-clock therapy possible, offering dosing convenience, flexibility, and relative steadiness of the opioid concentrations in the blood.1,2
    1. American Geriatric Society. Clinical Practice Guidelines. The Management of Chronic Pain in Older Persons. J Am Geriatr Soc. 1998;46:635-651.
    2. McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance compliance, quality of life, and analgesia. Am J Ther. 2001;8:181-186.
  • The efficacy of opioids in chronic pain has been established in a number of randomized, controlled trials, including placebo-controlled trials of controlled-release oral codeine1,2 and tramadol,3 immediate- and sustained-release oxycodone,4-6 intravenous and sustained-release oral morphine,7-11 and fentanyl.12
    In a comparison of transdermal vs oral delivery, transdermal fentanyl and sustained-release oral morphine were compared in a crossover trial. In this study, a significantly greater number of patients (35% vs 23%; P=0.002) considered pain control better with transdermal fentanyl than with morphine.8
    Peloso PM et al. J Rheumatol. 2000. 27:764-771.
    Arkinstall W, et al. Pain. 1995;62:169-178.
    Harati Y et al. J Diabetes Complications. 2000;14:65-70.
    Roth SH et al. Arch Intern Med. 2000;160:853-860.
    Caldwell JR et al. J Rheumatol. 1999;26:862-869.
    Watson CPN, Babul N. Neurology. 1998;50:1837-1841.
    Caldwell JR et al. J Pain Symptom Manage. 2002;23:278-291.
    Allen L et al. BMJ. 2001;322:1-7.
    Jamison RN et al. Spine. 1998;23:2591-2600.
    Moulin DE et al. Lancet. 1996;347:143-147.
    Rowbotham MC et al. Neurology. 1991;41:1024-1028.
    Dellemijn PL, Vanneste JA. Lancet. 1997;349:753-758.
  • In addition to “how does it work”, is it an opioid, is it not an opioid?
  • Depending where you look, affinity of M1 is ~1/10 of morphine
    5HT and NE involved in anitnociceptive effects of descending inhibitory pathways in CNS
  • This slide addressed the management of adverse events associated with therapy.1
    Side effects, shown above in random order, may include nausea, vomiting, itching, sedation, balance/ataxia (especially in older patients) and pruritus. Cognitive impairments/mental “clouding” may also occur. However, tolerance to these side effects typically occurs within a few days to weeks of therapy initiation. The most common side effect of chronic opioid therapy is constipation, which may persist, particularly if there are other predisposing causes.
    Once ruling out other causes, opioid side effects may be ameliorated by a number of approaches. For nausea, first try switching opioids and then try anti-emetics. For nausea associated with vertigo or movement, try antivertiginous agents (eg, scopolamine); for nausea associated with satiety, try metoclopramide.
    For sedation/somnolence, lower dose if possible; or add co-analgesics or psychostimulant agents. Modifications in the patient’s diet and activity levels may also be beneficial.
    For constipation, treat prophylactically with stool softeners, bowel stimulants, and nonpharmacologic measures or try switching opioids.
    Portenoy RK. Opioid analgesics. In: Portenoy RK and Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, PA: F.A. Davis Company;1996:248-253.
  • It is critical to once again address the importance of titration.Titration of dose is key to achieving optimal balance between therapeutic analgesics and side effects.
    Long-term administration of intrathecal opioids may also be associated with decreased libido, as a result of opioid effects on the hypothalamic-pituitary-gonadal axis (leading to hypogonadotrophic hypogonadism). Thus, such patients may need endocrine monitoring, consider testosterone replacement, or switching opioids; consider endocrine consultation.1-3
    Opioid therapy may be especially problematical in certain categories of patients—those engaged in high-risk activities or occupations and those with histories of substance abuse. Use caution and clinical judgment in these patients. Consultation with a pain specialist is recommended. It is useful to develop a relationship with a pain specialist—even prior to the occurrence of a need to refer.
    Abs R, Verhelst J, Maeyaert J, van Buyten J-P, Opsomer F, Adriaensen H, Verlooy J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000;85:2215-2222.
    Finch PM, Roberts LJ, Price L, Hadlow NC, Pullan PT. Hypogonadism in patients treated with intrathecal morphine. Clin J Pain. 2000;16:251-254.
    Roberts LJ, Finch PM, Pullan PT, Bhagat CI, Price LM. Sex hormone suppression by intrathecal opioids: a prospective study. Clin J Pain. 2002;18:144-148.
  • This slide addresses the issue aberrant drug-taking behaviors.
    Before considering initiation of opioid treatment, it is important for the physician, patient, and family to understand the distinction between physical dependence, tolerance, and addiction.
    Physical dependence is a pharmacologic effect characterized by the development of a withdrawal syndrome when an opioid drug is discontinued, when the dose is substantially reduced, or if an antogonist is administered. Dependence occurs in almost all patients on opioids and does not connote addiction.1
    Tolerance means that a greater amount of drug is needed over time to maintain a therapeutic effect. The number of patients who develop clinically relevant tolerance is unknown. Tolerance may also occur to side effects, and thus may be beneficial. Some patients who develop tolerance may be managed by judicious dose increases2; others who develop inexorable tolerance cannot be managed on opioids. There is no evidence to support a role for analgesic tolerance in the development of drug addiction. Addiction is, however, often though not always associated with tolerance.
    Pseudoaddiction refers to behaviors suggestive of addiction (eg, multiple prescribers, hoarding) when patients are undertreated for pain.1
    Addiction is a psychiatric disorder consisting of continued, compulsive use of the substance despite harm.1 The Diagnostic and Statistical Manual of Mental Disorders provides nine categories of opioid use or opioid-induced disorders, including diagnostic criteria for opioid dependence or opioid abuse.3
    True addiction (patient loss of control) may become obvious only when the physician stops prescribing the medicine. There is, however, little evidence that addiction is common within the chronic pain population. In a study reviewing the available data, it was found that prevalence estimates for addiction in patients with chronic pain ranged from 3% to 19%.4
    American Academy of Pain Medicine, American Pain Society, American Society of Addiction Medicine. Definitions Related to the Use of Opioids for the Treatment of Pain. 2001. Available at: Accessed October 2, 2002.
    Zenz M. Morphine myths: sedation, tolerance, addiction. Postgrad Med J. 1991;67:S100-S102.
    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th Ed. Rev Ed. Washington, DC: American Psychiatric Publishing, Inc.; 2000:269-277.
    Fishbain DA, Rosomoff HL, Rosomoff RS. Drug abuse, dependence, and addiction in chronic pain patients. Clin J Pain. 1992;8:77-85.
  • The tricyclic antidepressants have been found to be effective for treating a variety of pain states. These agents block the reuptake of both norepinephrine and serotonin and appear to have a variety of analgesic properties that extend beyond their modulation of serotonin and norepinephrine. Newer antidepressants—the selective serotonin reuptake inhibitors—do not have analgesic properties.
    They are used to treat headaches (including migraines), low back pain, fibromyalgia, painful diabetic neuropathy, postherpetic neuralgia, central pain, and cancer pain. These antidepressants appear to be most effective for treating burning pain or hypersensitivity, but also may be beneficial for lancinating neuropathic pain.
    Their use is limited by a greater incidence of adverse events. Class effects include sedation, orthostatic hypotension, and anticholinergic effects.
    Cohen SP, Mullings R, Abdi S, Warltier DC. The pharmacologic treatment of muscle pain. Anesthesiology. 2004;101:495–526.
    Macres S, Richeimer S, Duran P. Adjuvant analgesics. In: Warfield CA, Bajwa ZH, eds. Principles & Practice of Pain Medicine. 2nd ed. New York, NY: McGraw-Hill; 2004:627–38.
    National Pharmaceutical Council, Inc. Pain: Current Understanding of Assessment, Management, and Treatments. Reston, VA: National Pharmaceutical Council, Inc; 2001. Available at: Accessed September 8, 2004.
  • Brain:Cortex
    music, distraction
    placebo, opioids
    BS; endog opioids
    tonically active opioid sys med by 5hT and NE (monoamines)
  • Evolutionary standpoint: adapting a nervous system that could detect and remember danger
    In normal healing, as tissues heal, inflammation resolves and fewer signals are transmitted from the central nervous system (CNS), resulting in decreased pain and decreased muscle spasm.
    If normal healing does not occur, chronic pain may result, even in the absence of ongoing illness or after healing is complete. Plastic changes in the CNS following an acute injury may result in chronic, persistent pathologic pain.1
  • Pain management vels

    1. 1.     Shri Isari Velan Mission hospital  A comfort care center Provide comprehensive care to serious illness To live with comfort and dignity to life’s fullest extent A charitable Trust that provides patients the greatest comfort and peace of mind   
    2. 2.  “Palliative care is both a philosophy of care and an organized, highly structured system for delivering care. Palliative care expands traditional diseasemodel medical treatments to include the goals of enhancing quality of life for patients and family, optimizing function, helping with decision-making and providing opportunities for personal growth. As such, it can be delivered with life-prolonging care or as the main focus of care” ~ National Consensus Project for Quality Palliative Care, 2004
    3. 3. Life-prolonging and restorative treatments Hospice Palliative Care Disease Progression Diagnosis Bereavement Death Ferris F, Balfour H, Bowen K, Farley J, Hardwick M, Lamontagne C, Lundy M, Syme A, West P. A model to guide patient and family care. Based on nationally accepted principles and norms of practice. J Pain Symptom Manage. 2002;24(2):106-23.
    4. 4.     “There is nothing more that I can do.” “I don’t want to be the one to tell him.” “I can’t stop this treatment now, that would kill her. I wish we hadn’t started this.” “Continuing treatment in this case seems futile.”
    5. 5.     Pain Dyspnea/respiratory distress Nausea/vomiting Anorexia/cachexia      Pruritis/dermatitis Intractable seizures Delirium Incontinence Pressure ulcers
    6. 6.  Palliative care is appropriate for all patients with serious illness  The goal of palliative care is to enhance quality of life through assiduous symptom management and attention to psychological, social and spiritual needs of the patient and family  Palliative care is patient and family centered care  Hospice is both a philosophy of care and a Medicare benefit available to patients who are nearing the end of life
    7. 7. 9840474123
    8. 8. The Vedic chant "Sarve Santu Niramaya" meaning "may all be disease-free" has been the part of Hindu prayers for ages. Apart from Hinduism, every major religion has focussed on freedom from disease and PAIN.
    9. 9.       Define Pain Review Pain Physiology Review Evaluation of Pain and its effects Review Classes of Pain medications General Approach to Pain Management Prescriptions
    10. 10. Definition pain is an, unpleasant sensory and emotional experience associated with actual or potential tissue damage (IASP) Pain is a personal and subjective experience that can only be felt by the sufferer. Pain is whatever the experiencing person says it is and exists whenever they say it does.
    11. 11. Process of pain physiology nociceptor TRANSDUCTION TRANSMISSION PERCEPTION MODULATION
    12. 12.  Pain stimuli is converted to electrical energy known as Transduction. This stimulus sends an impulse across a peripheral nerve fiber (nociceptor).
    13. 13.  Biochemical mediators: “Chemical Soup” Prostaglandins Bradykinins Serotonin Histamines Cytokines Leukotrienes Substance P Norepinephrine
    14. 14. Transmission:  A delta fibers (myelinated) send sharp, localized and distinct sensations.  C fibers (unmyelinated) relay impulses that are poorly localized, burning and persistent pain.  Pain stimuli travel- spinothalamic tracts.
    15. 15.  Defined as: Projection of pain into the Central Nervous System
    16. 16.  A synapse contains three elements: the presynaptic terminal the synaptic cleft the receptive membrane
    17. 17. The presynaptic terminal is the axon terminal of the presynaptic neuron Here that the presynaptic neuron releases neurotransmitters which are found in vesicles
    18. 18. Peripheral Excitatory Mediators (Pain) Substance Receptor Mechanism Substance P NK1 ↑ neuronal excitability, edema (SP) Prostaglandin ? (PG) Bradykinin Sensitize nociceptors, inflammation, edema B2 (normal) Sensitize nociceptors B1 (inflammation) ↑ PG production H1 C-fiber activation, edema, 5-HT3 vasodilatation C-fiber activation, release SP Histamine Serotonin Norepinephrine α1 (NE) Sensitize nociceptors Activate nociceptors
    19. 19. Perception:  Person is aware of pain –somatosensory cortex identifies the location and intensity of pain  Person unfolds a complex reactionphysiological and behavioral responses is perceived.
    20. 20. Modulation:  Inhibitory neurotransmitters like endogenous opioids work to hinder the pain transmission.  This inhibition of the pain impulse is known as modulation
    21. 21. Pain pathway and modulation Ascending nociceptive pathways Interpretation in cerebral cortex: pain Stimulation of nociceptors (Aδ and C fibers) / Release of neurotransmitters and neuromodulators (i.e. PG) 1 Descending inhibitory controls / Diffuse noxious inhibitory controls Activation of serotoninergic and noradrenergic pathways Release of serotonin, noradrenalin and enkephalins at spinal level Injury 1. Adapted from: Bonica JJ. Postoperative pain. In Bonica JJ, ed. The management of pain. Philadelphia: Lea and Febiger;1990:461-80.
    22. 22. Do you think that how we conceptualize pain --PATHWAY vs DYNAMIC DISTRIBUTED SYSTEMS-- influences how we treat pain and the success of those treatments? PAIN PATHWAY Pain Seminar, Lecture #5, PAIN TREATMENTS, p.2 s ter n n e e… Pai er h
    23. 23. Let’s see… PAIN ? Pain Seminar, Lecture #45, PAIN TREATMENTS, p. 3
    24. 24.  The substances released from the traumatized tissue are: prostaglandins bradykinin serotonin substance P histamine
    25. 25.   Bradykinin- most potent pain producing chemical Prostaglandins- increase sensitivity to pain experience . Is a potent vasodilator and increase the production of bradykinin resulting edema
    26. 26.    Substance P- transmits pain impulses to brain centers and causes vasodilatation and edema Serotonin- causes pain by altering sodium flow—neuron to fire Histamine,Leukotrienes and nerve growth factor are released
    27. 27. Endorphins& Dynorphins- morphine like substances.  Located in the brain, spinal cord & GIT  Produce analgesia when attached with opiate receptors in the brain
    28. 28.  Gate control theory of pain is the idea that physical pain is not a direct result of activation of pain receptor neurons, but rather, its perception is modulated by interaction between different neurons
    29. 29.    Nerve fibers (A delta (fast channels)) and C fibers (slow channels) transmit pain impulses from the periphery Impulses are intercepted in the dorsal horns of the spinal cord, the substantia gelatinosa In this region, cells can be inhibited or facilitated to the T-cells (trigger cells)
    30. 30.   When cells in the substantia gelatinosa are inhibited, the ‘gate’ to the brain is closed When facilitated, the ‘gate’ to the brain is open
    31. 31.  Similar gating mechanisms exist in the nerve fibers descending from the thalamus and the cortex. These areas of the brain regulate thoughts and emotions. Thus, with a pain stimulus, one’s thoughts and emotions can actually modify the pain experience.
    32. 32.    Tissue damage activates free nerve endings (nociceptors) of peripheral nerves Pain signal is transmitted to the spinal cord, hypothalamus, and cerebral cortex Pain is transmitted to spinal cord by A-delta fibers and C fibers
    33. 33.    A-delta fibers transmit fast, sharp, well-localized pain signals C fibers conduct the pain signal slowly and produce poorly localized, dull, or burning type of pain Thalamus is the relay station for incoming stimuli, incl. pain
    34. 34.   A delta fibers found in the skin and muscle, myelinated, respond to mechanical stimuli. Produce intermittent pain. C fibers distributed in the muscle as well as the periosteum and the viscera. These fibers are unmyelinated, conduct thermal, chemical and strong mechanical stimuli. Produce persistent pain.
    35. 35. Parasympathetic responses  Decreased blood pressure  Decreased pulse  Nausea & vomiting  Weakness  Pallor  Loss of consciousness
    36. 36. Sympathetic responses  Pallor  Increased blood pressure  Increased pulse  Increased respiration  Skeletal muscle tension  Diaphoresis
    37. 37. Characteristic Acute Pain Chronic Pain Cause Generally known Often unknown Duration of pain Short, well-characterized Persists after healing, ≥3 mo Treatment approach Underlying disease Underlying disease and pain disorder
    38. 38. Physical Physical Psychological Psychological Total Pain Total Pain Spiritual Spiritual Social Social
    39. 39.     Nociceptive pain  Transient pain in response to noxious stimuli Inflammatory pain  Spontaneous pain and hypersensitivity to pain in response to tissue damage and inflammation Neuropathic pain  Spontaneous pain and hypersensitivity to pain in association with damage to or a lesion of the nervous system Functional Woolf. Ann Intern Med. 2004;140:441-451.
    40. 40. Nociceptive Pain Mixed Type Caused by a combination of both primary injury or secondary effects Caused by activity in neural pathways in response to potentially tissue-damaging stimuli Neuropathic Pain Initiated or caused by primary lesion or dysfunction in the nervous system CRPS* Postoperative pain Arthritis Mechanical low back pain Sickle cell crisis Sports/exercise injuries *Complex regional pain syndrome Postherpetic neuralgia Neuropathic low back pain Trigeminal neuralgia Central poststroke pain Distal polyneuropathy (eg, diabetic, HIV)
    41. 41. Is responsive to NSAID’s, coxibs, paracetamol and opiates Noxious Peripheral Stimuli Pain-Autonomic Response Heat - Withdrawal Reflex Cold Intense Mechanical Force Nociceptor Sensory Neuron Brain Chemical Irritants Spinal Cord Woolf. Ann Intern Med. 2004;140:441-451.
    42. 42. Somatic Pain • • • • Aching, often constant May be dull or sharp Often worse with movement Well localized Eg/ – Bone & soft tissue – chest wall
    43. 43. Visceral Pain • • • • Constant or crampy Aching Poorly localized Referred Eg/ – CA pancreas – Liver capsule distension – Bowel obstruction
    44. 44. Is responsive to NSAID’s,coxibs, paracetamol, and opiates Pain Inflammation Spontaneous Macrophage Mast Cell Neutrophil Granulocyte Pain Hypersensitivity -Allodynia -Hyperalgesia Nociceptor Sensory Neuron Brain Tissue Damage Spinal Cord Woolf. Ann Intern Med. 2004;140:441-451.
    45. 45. FEATURES OF NEUROPATHIC PAIN COMPONENT Steady, Dysesthetic Paroxysmal, Neuralgic DESCRIPTORS • • • • • Burning, Tingling Constant, Aching Squeezing, Itching Allodynia Hypersthesia EXAMPLES • Diabetic neuropathy • Post-herpetic neuropathy • Stabbing • trigeminal neuralgia • Shock-like, electric • may be a component of any neuropathic pain • Shooting • Lancinating
    46. 46. Spontaneous Pain Pain Hypersensitivity •May respond to • local anaesthetic • anticonvulsants • antidepressants Peripheral Nerve Damage •Less responsive to opioids Injury Spinal Cord Brain Stroke •No response to NSAID’s, coxibs, or . paracetamol Woolf. Ann Intern Med. 2004;140:441-451
    47. 47.  Functional pain Fibromyalgia, IBS etc.  Central neuropathic pain Poststroke , Spinal cord injury , Trigeminal neuralgia, and Multiple sclerosis .
    48. 48. Pain is inevitable. Suffering is optional. Andrew Parchman
    49. 49. Acute Pain Increased sympathetic activity GI effects Splinting, shallow breathing Increased catabolic demands Anxiety and fear Peripheral/ central sensitization Myocardial O2 consumption↑ GI motility↓ Atelectasis, hypoxemia, hypercarbia Poor wound healing/muscle breakdown Sleeplessness, helplessness Available drugs Myocardial ischemia Delayed recovery Pneumonia Weakness and impaired rehabilitation Psychological Chronic pain Courtesy of Sunil J Panchal, MD
    50. 50. Insomnia Sexual dysfunction Suicide risk Anxiety/ frustration/ irritability Depression Impaired relationships Low self-esteem Decreased productivity Decreased driving ability UNRESOLVED PAIN Reduced functional capacity Increased healthcare need/costs American Pain Foundation. Overview of Pain Surveys: Loss of income Inability to concentrate Fatigue
    51. 51.  Sensations         burning paresthesia paroxysmal lancinating electriclike raw skin shooting deep, dull, bonelike ache  Cardinal signs/symptoms  Allodynia: pain from a stimulus that does not normally evoke pain  thermal  mechanical  Hyperalgesia: exaggerated response to a normally painful stimulus
    52. 52.          Chemical excitation of non nociceptors Recruitment of nerves outside of site of injury Excitotoxicity- Dis inhibition of pain Sodium channels - abnormal Ectopic discharge Deafferentation – phantom pain Central sensitization  maintained by peripheral input Sympathetic involvement Antidromic neurogenic inflammation
    53. 53. Algesic sub Nociceptor Nociceptor Innocuous stimulus Na+ channels Pain sensation Adapted from Woolf CJ et al. Lancet. 1999;353:1959-1964.
    54. 54. Normal sensory function Aβ fiber mechanoreceptor Innocuous Na+ stimulus channel Na+ channel Weak synapse Nonpainful sensation Increased nociceptor drive leads to central sensitization of dorsal horn neurons Innocuous Na+ stimulus channel Na+ channel Increased synapsis strength Painful sensation Adapted from Woolf CJ et al. Lancet. 1999;353:1959-1964.
    55. 55. Visual Analog Scale Verbal Pain Intensity Scale No pain Mild Moderate Severe Very Worst pain pain pain severe possible pain pain Worst possible pain No pain 0–10 Numeric Pain Intensity Scale 0 1 No pain 2 3 4 5 6 Moderate pain 7 8 10 Worst possible pain Faces Scale 9 0 1 2 3 4 5 Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. FA Davis; 1996:8-10. Wong DL. Waley and Wong’s Essentials of Pediatric Nursing. 5th ed. Mosby, Inc.; 1997:1215-1216. 21 McCaffery M, Pasero C. Pain: Clinical Manual. Mosby, Inc. 1999:16.
    56. 56. The “Four A’s of Pain”   Activities of daily living  Adverse effects  20 Analgesia Aberrant drug-taking behaviors
    57. 57.    Pharmacotherapy and other medical/surgical care with appropriate medicine reorganization Restorative care including active physical and occupational therapy Psychological counseling utilizing cognitive-behavioral pain management strategies
    58. 58. Continual follow-up and monitoring are essential to good opioid analgesic therapy.  Reassess the “Four A’s of Pain”  analgesia  activities of daily living  adverse effects  aberrant drug-taking behaviors  Review treatment options 33
    59. 59. Titrate only one drug at a time
    60. 60. Modes of action of analgesics 1,2,3,4 Paracetamol ↓ Inhibition of central Cox-3 (?) (Inhibition of PG synthesis) Opioids ↓ Activation of opioid receptors Paracetamol ↓ Interaction with serotoninergic descending inhibitory pathway NSAIDs / Coxibs 1. D’Amours RH et al. JOSPT 1996;24(4):227-36. 2. Piguet V et al. Eur J Clin Pharmacol 1998;53:321-4. 3. Pini LA et al. JPET 1997;280(2):934-40. 4. Chandrasekharan NV et al. PNAS 2002;99(21):13926-31. ↓ Inhibition of peripheral and central Cox-1 / Cox-2 (Inhibition of PG synthesis)
    61. 61. 1. Medication must result in:  Significant pain relief  Tolerable side effects function
    62. 62. 2. Both physician & patient must realize significant individual variability
    63. 63. 3. Slow titration until either: a) Significant pain relief b) Intolerable side effects c) “Toxic serum level”
    64. 64. 4. Educate the patient
    65. 65. Satisfactory Symptom Management Opioid for moderate to severe pain + Non-opioid + Adjuvant Pain persisting or increasing Opioid for mild to moderate pain + Non-opioid + Adjuvant Pain persisting or increasing Mild Pain Non-opioid- NSAID + Adjuvant Pain
    66. 66. Factors that lower pain threshold Factors that raise pain threshold Discomfort Insomnia Fatigue Anxiety Fear Sadness Depression Boredom Introversion Mental isolation Social abandonment Relief of symptoms Sleep Rest Empathy Companionship Diversional activity Reduction in anxiety Elevation of mood Analgesics Anxiolytics Antidepressants
    67. 67.             NSAIDs/Cox-2 Paracetamol Steroidal Anti-inflammatory Drugs Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents
    68. 68. NA Cortico-Spinal Receptors Peripheral Nerve Copyright Dr Andrew Dean 5HT Spino-thalamic
    69. 69.    Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Steroidal Anti-inflammatory Drugs Miscellaneous Drugs Pharmacological control of inflammation: Preventing the release of inflammatory mediators  Inhibiting their actions  Treating pathophysiologic responses to them 
    70. 70. General characteristics  Drugs that inhibit one or more steps in the metabolism of arachidonic acid (AA)  Aspirin-like drugs or COX inhibitors Major action:  inhibit Cyclooxygenase (COX) Pharmacological effects  Suppress inflammation  Relieve pain  Reduce fever
    71. 71. Tissue Trauma Cell Membrane Phospholipids Phospholipase Arachidonic Acid C O X Cyclo-oxygenase Endoperoxides Toxic Oxygen Radicals Thromboxane Prostaglandins Prostacyclin
    72. 72. (phospholipids) Cell Membrane phospholipase A2 Lipoxygenase (LOX) Arachidonic acidLeukotrienes cyclooxygenase indomethacin aspirin, (COX1 & COX2) PGH2) prostacyclin thromboxane synthetase synthetase prostacyclin Thromboxane A2 Cyclic endoperoxides (PGG2, prostaglandin synthetase PGE2 PGF2α
    73. 73.  Salicylic acid derivatives        Ibuprofen Naproxen Ketoprofen Flunixin meglumine Hydroxamic acid derivatives   Piroxicam Meloxicam Nicotinic acid derivatives   Phenylbutazone Dipyrone Oxicams   Etodolac Ketorolac Propionic acids     Meclofenamic acid Tolfenamic acid Pyrazolones or enolic acids   Indomethacin Pyranocarboxylic acids    Acetaminophen Indole and indene acetic acids Fenamates   Aspirin Para-aminophenol derivatives   Tepoxalin Coxib-class NSAIDs
    74. 74.  Cyclooxygenase has 2 forms:  COX-1 (good COX) : found in all tissues  Mediates “housekeeping chores”  Protect gastric mucosa  Support renal function  Promote platelet aggregation  COX-2 (bad COX) : found at sites of tissue injury  Mediates inflammation and sensitize receptors to painful stimuli  Also present in brain- mediates fever and
    75. 75.  COX-1 inhibition  Results largely in harmful effects  Gastric erosion and ulceration  Bleeding tendencies  Acute renal failure  Results in some beneficial effects  Protection against myocardial infarction  COX-2 inhibition  Results in beneficial effects  Suppression of inflammation  Alleviation of pain
    76. 76.  Drugs with anti-inflammatory properties NSAIDs—Nonsteroidal anti-inflammatory drugs: 2 types  First generation (inhibit both COX1 and COX2) Non-selective COX inhibitors - aspirin  Second generation (inhibit COX2 only) Preferential COX2 inhibitors (partial specificity for COX2) - celecoxib (human drug) Selective COX2 inhibitors (full specificity for COX2) - rofecoxib (human drug)
    77. 77.  NSAIDs act to block the first step of prostaglandin synthesis by binding to and inhibiting cyclooxygenase   Dose and drug dependent The major therapeutic, toxic, and potency of NSAIDs
    78. 78.  Ratio of COX1 to COX2 (COX1:COX2 ratio)  describes the amount of drug necessary to inhibit the respective isoform of the cyclooxygenase enzyme (IC50)  Calculation: COX1:COX2 ratio = IC50COX1 / IC50COX2   COX1 to COX2 ratio > 1 is desirable, or COX2 to COX1 ratio < 1
    79. 79. Examples        Aspirin 0.343 Carprofen (racemix mixture) 129 Carprofen (S isoform) 181 Carprofen (R isoform) 4.19 Etodolac 0.517 Flunixin meglumine 0.635 Ketoprofen
    80. 80.      As weak acids, well absorbed after PO Small volume of distribution (10%) Highly protein binding (90%) Clearance: hepatic metabolism both phase I and II Conjugated metabolites -> urine
    81. 81.   Analgesia, antipyresis, and control of inflammation Relative potency in lab animals and human Meclofenamic acid > indomethacin > naproxen > aspirin  Relative potency in horses Flunixin meglumine >
    82. 82.  Gastrointestinal system   GI ulceration Hematopoietic system Bleeding dyscrasias  All NSAIDs are able to impair platelet activity  Platelet aggregation defects caused by aspirin can last up to 1 week   Renal system Analgesic nephropathy  In kidney, vasodilatory and tubuloactive prostaglandins are protective 
    83. 83.      GI damage is the most common and serious side effect of NSAIDs Dogs – very sensitive Inhibition of COX1-stimulated PGE2-mediated bicarbonate and mucous secretion, epithelialization, and increased blood flow Direct irritation of acidic drugs Salicylates cause backdiffusion of
    84. 84. Non-Selective COX inhibitors           Acetaminophen Aspirin Etodolac Flunixin Meglumine Ketorolac Naproxen Phenylbutazone Piroxicam Tolfenamic acid Vedaprofen Preferential COX-2 inhibitors (Partial specificity for COX-2)   Carprofen Meloxicam Selective COX-2 inhibitors (no significant effect on COX1)     Deracoxib Firocoxib Robenacoxib Mavacoxib Dual COX and LOX inhibitors  Tepoxalin
    85. 85.   Most frequently used and misused drugs in medicine Needs an understanding of their actions on all body systems
    86. 86. Corticotropinreleasing factor (CRF) Adrenocorticotropic hormone (AC
    87. 87.  Glucocorticoid receptors  Intracellular,  3 subtypes at least activated receptor-glucocorticoid complex  -> binds to glucocorticoid responsive element  -> modulate gene transcription  Target proteins could be induced or inhibited  result in pharmacologic effects of glucocorticoids  Differential gene regulation by
    88. 88. Induced     Inhibited Lipocortin-1 Cytokines Beta2-adrenoreceptor Natural killer receptor Angiotensin-converting enzyme Inducible nitric oxide synthase Neutral endopeptidase Cyclooxygenase Endotheslin Phospholipase Collagenase
    89. 89.   Protect glucose-dependent tissues (brain, heart) Hyperglycemic effect  Increase gluconeogenesis, insulin antagonism  Increased breakdown of proteins  Skeletal muscles and collagen  Provides gluconeogenic precursors  Result in muscle wasting, delayed wound healing, and thinning of the skin  Promote lipolysis
    90. 90.  Increase the RBC content of the blood  Retarding     Lymphopenia Eosinopenia Monocytopenia Neutrophilia  Increased marrow  erythrophagocytosis release from bone This blood cell profile: Stress
    91. 91.      Inhibit early and late phases of the inflammation Inhibit edema formation, fibrin deposition, leukocyte migration, phagocytic activity, collagen deposition, and capillary and fibroblast proliferation Inhibit enzyme phospholipase A2 and COX-2 Inhibit release of TNF-α, IL-2, and platelet activating factor Inhibit inducible nitric oxide synthase
    92. 92.  Absorption  Several products are well absorbed orally  Topical use -> well absorbed  Long-term use - > systemic effect  Metabolism  Eliminated by oxidation or reduction, and followed by conjugation
    93. 93.  Duration of action AntiInflam potency Short acting (< 12 hr)  Hydrocortisone 1  Topical use  (identical to cortisol) Intermediate acting  Prednisolone (12 – 36 hr) and Prednisone 4  Methylprednisolone (has lipid antioxidant activity) 5  Triamcinolone 5  Alternate day administration
    94. 94.          Iatrogenic adrenocortical insufficiency Iatrogenic hyperadrenocorticism Susceptibility to infection Glucocorticoid-induced polyphagia Muscle weakness and muscle atrophy Reversible hepatopathy Polyuria and polydipsia Pulmonary thromboembolism Hypertension
    95. 95.            NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents
    96. 96.       Effective in treating a variety of pain states Block the reuptake of norepinephrine (and 5HT), which modulates pain Analgesia at lower doses than antidepressant effect Use limited by side effects (anti-cholinergic) Amitriptyline vs desipramine Caution: coronary disease
    97. 97. Tricyclic SSRI Other Amitriptyline (Elavil®) Fluoxetine (Prozac®) Nefazodone (Serzone®) Desipramine (Norpramin®) Paroxetine (Paxil®) Venlafaxine (Effexor®) Doxepin (Sinequan®) Sertraline (Zoloft®) Trazodone (Desyrel®) Imipramine (Tofranil®) Fluvoxamine (Luvox®) Nortriptyline (Pamelor®) Citalopram (Celexa) *Partial list SSRI = selective serotonin reuptake inhibitor Bupropion (Wellbutrin®)
    98. 98. Meta-analysis by Onghena (1992) Diagnosis Synthesis by Magni (1991) No. of Studies Effect Size Diabetic neuropathy 1 1.71 Responsive Postherpetic neuralgia 2 1.44 Responsive Tension headache 6 1.11 Responsive Migraine 4 0.82 Responsive Atypical facial pain 3 0.81 Responsive Chronic back pain 5 0.64 Minimal clinical benefit Rheumatological pain 10 0.37 Fibrositis responsive; Osteo- and rheumatoid arthritis probably responsive Not specified or mixed 7 0.23 Probable effect
    99. 99.            NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents
    100. 100.       Carbamazepine* Divalproex sodium* Gabapentin Pre Gabalin Clonazepam Phenytoin       Lamotrigine Topiramate Zonisamide Oxcarbazepine Levatriacetam Tiagabine
    101. 101.      Demonstrated effectiveness in variety of neuropathic pain states Reduce firing of sensory neurons Agents: Carbamazepine, phenytoin, gabapentin, lamotrigine No ceiling dose: Start low and titrate upward until adverse effects appear Adverse effects vary  Most common are sedation, mental clouding, dizziness, nausea, unsteadiness
    102. 102.  Postherpetic neuralgia  gabapentin  pregabalin   Diabetic neuropathy carbamazepine  phenytoin  Gabapentin  pregabalin  lamotrigine   lamotrigine Trigeminal neuralgia carbamazepine  lamotrigine  Oxcarbazepine  Pregabalin  *Not approved by FDA for this use. 43 HIV-associated neuropathy   Central poststroke pain  lamotrigine
    103. 103.      Chemically related to gabapentin  used for treating pain caused by neurologic diseases such as postherpetic neuralgiaas well as seizures and treating fibromyalgia. The mechanism of action of pregabalin is unknown. Pregabalin binds to calcium channels on nerves and may modify the release of neurotransmitters. Reducing communication between nerves may contribute to pregabalin's effect on pain and seizures. 
    104. 104.            NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents
    105. 105.   Clonidine Tizanidine
    106. 106. Oral or transdermal Clonidine:  Enhance the effect of narcotics  Decreases the daily narcotic requirement  Excellent Adjuvant therapy for narcotic dependent patients  Effective for neuropathic pain
    107. 107.        Trigeminal neuralgia (Fromm 1993) Chronic low back pain(Berry 1988) Cluster headache (D’alessandro 1996) Chronic tension-type headache (Nakashima 1994) Spasmodic torticollis (Houten 1984) Neuropathic pain Chronic headache(2002)
    108. 108.            NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents
    109. 109. Mu-Opioid-R Activation Nerve Injury NMDA-R Inhibitors PKC ↑ Excitability Neurotoxicity Hyperalgesia ↓ Mu-Efficacy Mu-Opioid Tolerance
    110. 110.       Dextromethorphan Ketamine d-Methadone Amantadine Memantine Amitriptyline
    111. 111.            NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents
    112. 112.      Cyclobenzaprine Carisoprodol Methocarbamol Metaxalone Orphenadrine citrate
    113. 113.     Structurally similar to tricyclics Centrally acting Nocturnal muscle spasm effects Side effects:  Drowsiness - Cardiac dysrhythmias  Anticholinergic  Dry mouth  Blurred vision  Urine retention  Constipation  Increased intraocular pressure
    114. 114.     Precursor of meprobamate Centrally active Reduction of muscle spasm Side effects:  Sedation, drowsiness, dependence  Withdrawal symptoms  Agitation  Anorexia  N/V  Hallucination  Seizures
    115. 115.      Investigative usage: MS Daily dosage: 1000 mg qid Side effect: drowsiness Mechanism of action:  Centrally active  Inhibits polysynaptic reflexes Clinical effects:  Reduction of muscle spasms
    116. 116.    Daily dosage: 400-800 mg tid Clinical effects:  Reduction in muscle spasm Side effects:  Nausea  Drowsiness  Dizziness
    117. 117.      Investigative usage: SCI Daily dosage: 100 mg bid Analog of diphenhydramine Given IV for antispasticity trials Side effects:  Anticholinergic  Rare aplastic anemia
    118. 118.            NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents
    119. 119.  Topical agents are active within the skin, soft tissues and peripheral nerves.  In contrast to transdermal, oral or parenteral medications, use of a topical agent does not result in clinically significant serum drug levels.  Other benefits include lack of systemic side effects and drug-drug interactions.  The mechanism of action of a topical analgesic is unique to the specific agent considered.
    120. 120.       Aspirin preparations  eg, aspirin in chloroform or ethyl ether Capsaicin Local anesthetics - lidocaine patch 5%/eutectic mixture of local anesthetics Tricyclic antidepressants Opiates ( Buvalor, Fentenyl ) Investigational agents
    121. 121.   Salicylic acid derivative (a.k.a. wintergreen oil, sweet birch oil) Lipid solubility increases toxicity More toxic than aspirin  1 teaspoon (5ml) wintergreen oil contains 4,000 mg salicylate  30ml wintergreen oil is a fatal dose in adults   Risk of toxicity reduced with use for acute pain, limited to a small area of dermal application Chyka, P.A., et al., 2007
    122. 122.    Neuropathic pain states studied include: diabetic neuropathy, PHN, post-mastectomy pain, HIV neuropathy. Non-neuropathic pain states such as osteoarthritis have been studied as well. Efficacy demonstrated in some of these studies but limited by adverse effects and compliance issues..
    123. 123.      Low back pain Osteoarthritis Chronic myofascial pain Acute soft tissue injury pain Post-operative pain
    124. 124.  1.     Galeotti N, DeCesare Mannelli L, Mazzanti G, et al. Menthol: a natural analgesic compound. Neurosci Lett 2002 Apr 12;322(3):145-148. This article is particularly interesting as the authors review evidence which suggests that one of the mechanisms of analgesia for menthol, a common ingredient in over the counter preparations may actually be the activation of kappa opiate receptors.
    125. 125. Menthol generates analgesic activity through:  Ca2+ channel blocking activity  Binding to kappa opioid receptors Stanos, S.P., 2007
    126. 126.  Effect of topical morphine for mucositisassociated pain following concomitant chemoradiotherapy for head and neck carcinoma. (Cerchietti LC, Navigante AH, Bonomi MR, et al., Cancer 2002 Nov 15;95(10): 2230-6.) Patients (n=26) with cancer-related mucositis treated with topical morphine or topical lidocaine/ diphenhydramine/ magnesium topical solution.
    127. 127.            NSAIDs/Cox-2 Acetaminophen Antidepressants Anticonvulsants Oral local anesthetics Alpha adrenergic agents Neuroleptics NMDA receptor antagonists Muscle relaxants Topical analgesics Emerging Agents
    128. 128.     Botulinum Toxin (Type A, Type B) New intraspinal agents Thalidomide Topical antidepressants
    129. 129.   Special issues Evidence for efficacy
    130. 130. Altered behavioral response to pain and diminished ability to perceive pain impulses without loss of consciousness. Opioid Analgesic Actions: Analgesia Decreased G.I. Motility Respiratory Depression Euphoria Classes of Analgesics: NCH 3 H OH O OH Morpheus - son of Hypnos Non-narcotic – e.g. aspirin, ibuprophen, etc. Act mainly in the periphery as anti-inflammatories with some CNS activity as well. Narcotic/Opioids – Analgesic action is in the CNS. Morphine is the prototype (From “Morpheus” Greek god of dreams). Opium is the juice from the poppy and has been used for thousands of years to relieve pain.
    131. 131. "Among the remedies which it has pleased Almighty Godto give to man to relieve his sufferings, none isso universal and so efficacious as opium."Thomas Sydenham(1624 1689) 17th century engraving of man in Eastern dress collecting juice from the buds of poppy plants He was among the first to describe scarlet fever, differentiating it from measles and naming it, and to explain the nature of hysteria and St. Vitus' dance (Sydenham's chorea). Sydenham introduced laudanum (alcohol tincture of opium) into medical practice, was one of the first to use iron in treating irondeficiency anemia, and helped popularize quinine in treating malaria. Derided by his colleagues, Sydenham benefited immensely from a consequent
    132. 132. Early victims of the War On Drugs. A battle-scene from the First Chinese Opium War (1839-42)
    133. 133.  Central Mu  respiratory depression  analgesia  euphoria  miosis  Peripheral Mu  cough suppression  constipation
    134. 134. Small peptides. β-endorphin is a 31 amino acid peptide. Examples: Tyr – Gly –Gly – Phe – Met ( Met Enkephalin) Tyr – Gly –Gly – Phe – Leu ( Leu Enkephalin)
    135. 135. •Similar activity to the opioids (analgesia) •Similar addiction and withdrawal effects •Enkephalins are antagonized by opioid antagonists (same receptor) •Enkephalins are rapidly inactivated by specific peptidases in the brain. Details of Enkephalin Mechanism •Enkephalinergic system exists to modulate pain. •Enkephalin release inhibits adenylate cyclase, decreasing cAMP levels and causing a K+ efflux that hyperpolarizes the “pain neuron”, which inhibits nerve cell activity. Opioids also bind the enkephalin post-synaptic receptors. •Enkephalinergic neurons have an “auto-receptor” that can bind enkephalin or exogenous opioids. •Opioid binding to the “auto-receptor decreases enkephalin release, this results in tolerance,
    136. 136. Second Messenger Effects Opioids and Enkephalins inhibit cAMP synthesis by inhibiting adenylate cyclase. The physiological response is to make more enzyme to compensate. Tolerance develops. When opioids are removed, an excess of AC is available and now active, overstimulation produces withdrawal. Opioid antagonists don’t cause withdrawal symptoms in naive subjects. Enkephalin SAR L-tyrosine is required along with a terminal NH2. D-tyrosine is inactive Phe is very important, partial or full loss of activity occurs upon substitution D-amino acids at other positions, particularly the Gly’s decrease hydrolysis and therefore increase potency. D-amino acids and bulky amino acids affect activity and may increase receptor selectivity Rigid analogs are useful for assessing preferred conformations and may be more selective for different receptors.
    137. 137. All bind morphine and endogenous enkephalins, all are antagonized by naloxone µ is the analgesic receptor. µ2 subtype is associated with respiratory depression and with GI receptors. δ may be the antitussive receptor for codeine and related compounds. The antitussive actions of µ and δ specific agonists are antagonized by naloxone. However dextromethorphan sites don’t bind codeine, and binding at these sites (likely σ sites) are not antagonized by naloxone. Therefore, there are at least two antitussive receptors. J. Pharm. And Exp. Therapeutics (2000) 292, 803-809 κ is also analgesic. Binding site of several mixed agonist/antagonist compounds. Pentazocine – agonist at κ, antagonist at µ Buprenorphine – partial agonist at µ (slowly dissociates), antagonist at κ Butorphanol – agonist at κ, antagonist at µ
    138. 138. κ agonists produce psychotomimetic/dysphoric side effects similar to those seen with the σ receptor agonist PCP. High doses of pentazocine have this effect. σ and κ receptors are not analgesic on their own, but specific κ agonists do cause analgesia. Nature (1996) 383, p.759; pp.819-823. µ knockout does not produce analgesia with morphine, Perhaps µ/δ, µ/κ receptors interact. κ binding could induce activity in µ receptors. Other points: µ (MOR) knockouts are fully functional, no adverse side effects. Conclusion: opioid system is not active under normal resting conditions. That’s why you don’t get addicted to your own enkephalins.
    139. 139. Opioids have excitatory effects in multiple regions of the nervous system. Excitation by opioids is generally attributed to inhibition of inhibitory pathways (disinhibition). However, recent studies indicate that opioids can directly excite individual cells. These effects may occur when opioid receptors interact with other G protein coupled receptors, when different subtypes of opioid receptors interact, or when opioids transactivate other receptors such as receptor tyrosine kinases. Changes in the relative level of expression of different receptors in an individual cell may therefore determine its functional response to a given ligand. This phenomenon could represent an adaptive mechanism involved in tolerance, dependence and subsequent withdrawal. From inhibition to excitation: Functional effects of interaction between opioid receptors Life Sciences Volume 76,, (2004), Pages 479-485
    140. 140. “Discouraging data on the antidepressant.”
    141. 141.  Mechanism—variations on opioid receptor agonists, mixed agonist  Route—PO, PR, IV, IV-PCA, IM, transdermal, transmucosal, epidural/ intrathecal  Side effects—sedation, respiratory depression, n/v, constipation, itching
    142. 142.  Contraindications  Relative—COPD, hypotension, impaired renal function, impaired liver function, elderly patients  Absolute—Hypersensitivity, paralytic ileus, respiratory depression
    143. 143.     6 Era of “Balance” Growing recognition that opioids are essential for chronic pain Potential risks are serious but can be managed The goal: maximize symptom relief and functional improvement while minimizing addiction, diversion, and side effects
    144. 144.        Titrate gradually Determine cause of symptoms Change dosing route or regimen Switch to another opioid Add an adjuvant and reduce dosage Eliminate other nonessential agents Assume that constipation will occur and provide preemptive treatment
    145. 145. • Categories – acute pain – cancer pain – chronic (persistent) noncancer pain • Temporal pattern – episodic/continuous • Mechanisms – nociceptive (somatic or visceral) 9 – neuropathic (peripheral or central)
    146. 146.  16 Short-acting opioids  morphine sulfate (eg, Morcontin Morcon )  Codeine  Tramadol ( Eg Dolmundin )  fentanyl  Buprenorphine * May contain additional active ingredient.
    147. 147.    Gold Standard Used for severe pain Hepatic metabolism 45% to 55% to morphine-3-glucuronide, which produces hyperalgesia, allodynia, hyperactivity  10% to 15% to morphine-6-glucuronide, which has greater analgesic properties, fewer adverse effects 
    148. 148. (NR) H3CN 14 Modifications of both 3 and 6 positions (hydroxyls). R= O O CCH 3 R= 6 3,6-O-diacetylmorphine, 2 x morphine. (Heroin) OH (R1) O 2 O CCH 3 7 H 1 O 8 3 OH (R) Greater euphoria, higher addiction liability. Probably metabolized to 6-Oacetate then morphine in CNS. HEROIN A powerful remedy for coughs NCH 3 NCH 3 H H O O CH3 O O O OH O CH3 O
    149. 149. We need analgesics with less respiratory depression that are also less addictive. Morphinans. NCH 3 NCH 3 H H OH OH H OH H OCH 3 levorphanol (Levo-Dromoran) (-) isomer is an active analgesic, 5 x morphine (+) isomer is an active antitussive (dextrorphanol) and a poor analgesic N H (+) or (d) dextromethorphan Antitussive activity similar to codeine, no analgesic activity, no addiction liability. butorphanol (Stadol) 4 x morphine as agonist 1 x morphine as antagonist -low(er) addiction liability “better for acute pain”
    150. 150. Benzomorphans. Pentazocine (Talwin) N Mixed agonist/antagonist. Used as an agonist for pain. 1/3 x morphine. Low addiction. H3C CH 3 OH 4-phenyl piperidines. Completely synthetic CH3 O OCH 2 CH3 NCH 3 N H NCH 3 OH OCH2 CH 3 O O OH Meperidine Meperidine Morphine
    151. 151. 4-phenyl piperidine SAR. •Phenyl and piperidine rings are required. •3° Nitrogen is optimal. Nitrogen substituent containing a phenyl group increases potency (fentanyl). •You can’t make an antagonist by substituting the nitrogen. •Addition of a meta hydroxyl to the aromatic ring increases potency and addiction (analogous to morphine) •C-4 is usually quaternary. Alkyl esters are common for this class. Placing a nitrogen between the rings increases potency (fentanyl again) Properties of Phenylpiperidines. Bemidone – 3 x Meperidine α-Prodine (Nisentil) – 2 x Meperidine. Not used anymore Fentanyl (Sublimaze) – ~50-100 x Morphine. Fast onset, short duration. Used as an analgesic and also as an anesthetic either with or without droperidol. (About 500 x Meperidine analgesic potency). Diphenoxylate – Antidiarrheal – Not analgesic at therapeutic doses and can be dispensed with Atropine Loperamide (Imodium) – Polar groups decrease intestinal absorption and eliminate CNS activity. Inhibits GI muscle contraction by interaction with opioid receptor.
    152. 152. OCH2 CH3 O NCH3 O OCH2 CH3 HO N Bemidone CN OCH 2 CH 3 O Diphenoxylate NCH 3 H3 C α-prodine O HO O Cl N CH 2 CH 3 N N Loperamide Fentanyl F N O N O N Droperiodol (a butyrophenone, not a phenylpiperidine) N(CH3 )2
    153. 153. 3,3- Diphenylpropyl amines. Methadone 1x morphine less sedative longer acting. 1, 1.5 day half-life. 1 dose every 72 hours will prevent heroin withdrawal Propoxyphene d isomer (Darvon) – analgesic with 1/2 the potency of codeine l isomer (Novrad) – antitussive action only. CH 3 C CH 3 CH 3 CH 2 CH N CH 2 CH 2 CH 3 Methadone CH CH 2 N O CH 3 O C CH 3 O CH 2 CH 3 Propoxyphene (d or l isomer) CH 3
    154. 154. O O O N O O O N N N O N N N N N N O O O O Remifentanil Alfentanil Fentanyl O N O O N N N S Sufentanil Carfentanil Fentanyl - Actiq (fentanyl on a stick), Duragesic transdermal patches (12, 25, 50, 100 µg/h) Therapeutic index=400, morphine = 70 Alfentanil - Ultra-short acting, 5-10 minutes analgesic duration Remifentanil - Shortest acting opioid - 1/2 time is 4-6 minutes. Used in MAC anesthesia. TI=30,000 Sufentanil - 5-10x Fentanyl, used for heart surgery. Carfentanil - (100x Fentanyl) Thought that it was used in the 2002 Moscow theater crisis to subdue Chechen hostage takers. Didn’t turn out so well. 42 terrorists and 130 hostages died. Works well on bears.
    155. 155.       Greater risk of inducing seizures than other opioids No proof of greater effectiveness May be associated with cardiac conduction abnormalities (not reversible by naloxone) Should not be used in the elderly No longer used in United Kingdom 1/30/09: FDA Advisors voted to recommend banning propoxyphene.
    156. 156.   MOA: exerts its analgesic effect via high affinity binding to μ opiate receptors in the CNS; displays both agonist and antagonist activity Possible advantages:  It has a lower abuse potential  is less dangerous in an overdose  causes fewer withdrawal symptoms when it's stopped. 
    157. 157.  Analgesic activity   0.3 mg of parenteral buprenorphine =10 mg of parenteral morphine Prescribing restrictions MDs with special training to use for opioid addiction outside of a clinic: DEA # starts with “X”.  MDs using for pain do not need “X” in DEA.   Encourage them to write “for pain” on rx.
    158. 158.  A weak opioid agonist effective in moderate to moderately severe pain    Also inhibits reuptake of 5HT and NE Reduced risk of respiratory depression, physical dependence, and abuse Most common adverse events are dizziness, nausea, constipation, somnolence
    159. 159.  17 Long-acting opioids  methadone  sustained-release morphine  transdermal Buprenorphine / fentanyl
    160. 160.  18 Efficacy of opioids in chronic noncancer pain established in a number of randomized, controlled trials, including placebo-controlled trials of:  codeine  tramadol  morphine  fentanyl  Buprinorphone
    161. 161.      How does tramadol work? Which patients might it benefit? Is it better tolerated than other analgesics? Does it have abuse potential? Where does it fit in the analgesic continuum?
    162. 162.  Weak µ-opioid receptor effects  Structurally related to morphine and codeine  ~10-fold less affinity for µ receptor than codeine and up to 6000-fold less than morphine  Metabolized to highly active M1→ 300-fold greater affinity than parent compound   Analgesia only partially blocked by naloxone (~33%) Serotonin and norepinephrine reuptake inhibition Effect reduced by > ½ by adrenergic receptor antagonist  Less than that with imipramine  Grond S, et al. Clin Pharmacokin 2004;43:879-923. Raffa RB. J Clin Pharm Therap 2008;33:101-8.
    163. 163.   Acute Pain Chronic Pain Osteoarthritis  Neuropathic Pain  Low back pain 
    164. 164.    Nausea and vomiting  switch opioids; anti-emetics Sedation  lower dose if possible; add co-analgesics; add stimulants Constipation  treat prophylactically with stool softeners, bowel stimulants, and nonpharmacologic measures; switch opioids 34
    165. 165.    35 Itching  switch opioids; antihistamines Endocrine dysfunction/decrease in libido  switch opioids; endocrine monitoring; testosterone replacement; endocrine consultation Addiction  refer for comprehensive assessment
    166. 166.  Physical dependence: a withdrawal syndrome would arise if a drug is discontinued, dose is substantially reduced, or antagonist is administered  Tolerance: a greater amount of drug is needed to maintain therapeutic effect, or loss of effect over time
    167. 167.  Pseudoaddiction: behavior suggestive of addiction caused by undertreatment of pain  Addiction (psychological dependence): a psychiatric disorder characterized by continued compulsive use of a substance despite harm
    168. 168. What is the difference between physical dependence, tolerance, and addiction?
    169. 169.  Tolerance No “high” (opioids are metabolized differently as they address the pain)  Usually some physical tolerance and dependency to pain medications develop   Addiction Psychological “high” Intention to harm the body Negative personal, legal or medical consequences
    170. 170.  Addiction: Usage is out of control  Obsession with obtaining a supply  Quality of life does not improve   Pseudo-Addiction From under-treatment of pain Drug-seeking/Crisis of mistrust Behavior and function improve when pain is relieved
    171. 171.    Numerous pharmacotherapeutic options are available for the management of chronic pain. Proper evaluation including pain assessment is key to providing the best analgesic approach. Optimizing analgesia in the long term requires achieving a proper balance among efficacy, adverse effects, cost and other factors.
    172. 172. 1) 2) 3) Inhibit sustained high-frequency neuronal firing by blocking Na+ channels after an action potential, reducing excitability in sensitized C-nociceptors. Blockade of Na+ channels and increase in synthesis and activity of GABA, in inhibitory neurotransmitter, in the brain. Modulates Ca+ channel current and increases synthesis of GABA. Deglin, J.H. & Vallerand, A.H., 2001
    173. 173.       Effective in treating a variety of pain states Block the reuptake of norepinephrine (and 5HT), which modulates pain Analgesia at lower doses than anti-depressant effect Use limited by side effects (anti-cholinergic) Amitriptyline vs desipramine Caution: coronary disease
    174. 174. Beydoun A, Backonja. J Pain Symp Management 2003.
    175. 175. Transmission via spinothalamic tract to brain Dorsal horn Ion fluxes Tissue injury (H+/ K+) Dorsal root ganglion Bradykinin Prostaglandins Leukotrienes Spinal cord Substance P To brain Histamine Substance P, aspartate, neurotensin, glutamate Sensitized nociceptor
    176. 176.      Increase peripheral input: increase DH firing Increase firing: increased NMDA, Ca, PKC, Nitric Oxide Increase PKC, Ca: genetic changes Increase NO: decreased GABA neurons Increase Neurotrophins: sprouting Cousins, MJ, 2009 AAPM
    177. 177. Injury Acute Pain Normal Healing Pain Relief Healing With Plasticity Allodynia Hyperalgesia Chronic Pain Adapted from Marcus DM. Am Fam Physician. 2000;61:1331-1338.