Opioid pharmacology
•
1 like•199 views
Opioids work by binding to opioid receptors located throughout the body. There are several types of opioids that bind to receptors in different ways, producing varying effects. While opioids are effective analgesics, they can cause numerous side effects that must be carefully monitored and managed. Long term opioid therapy requires consideration of addiction risk, aberrant behaviors, and strategies to minimize dependency issues while providing pain relief.
Recommended
More Related Content
Viewers also liked
Viewers also liked (18)
Similar to Opioid pharmacology
Similar to Opioid pharmacology (20)
Recently uploaded
Recently uploaded (20)
Opioid pharmacology
- 2. TerminologyTerminology • Opioids: refers broadly to all compounds that work at the opioid receptors • Narcotics: derived from the Greek word for stupor. – Once used to describe medications for sleep – Then used for opioids – Now a legal term for drugs that are abused
- 3. Opioid ReceptorsOpioid Receptors Receptors are located on the brain, spinal cord, gut, peripheral nerves, and peripheral tissues • Mu (mu1 and mu2) – Mediates the analgesic effects and most of the side effects of MSO4 • Miosis, bradycardia, respiratory depression, constipation, histamine release • Strong naloxone sensitivity • Kappa (K1and K2 and K3) • Sedation • Intermediate naloxone sensitivity • Sigma • Mydriasis, delirium, dysphoria • ? No naloxone sensitivity
- 5. EndorphinsEndorphins • Identification of opioid receptors lead to the discovery of “endogenous morphines” β endorphin (31 amino acids)-ε receptor γ endorphin (17 amino acids)-ε receptor – Leu-enkaphalin (5 amino acids)-δ receptor – Met-enkephalin (5 amino acids)-δ receptor – Dynorphin (17 amino acids)-κ receptor – Methorphamide (7 amino acids)-µ receptor
- 9. Classification of OpioidsClassification of Opioids • Full Agonists - bind opioid receptors – MSO4 • Partial Agonists- bind opioid receptors at a lower level – Buprenorphine, etorphine • Mixed agonist/antagonists - agonist effect at one receptor and antagonist effect at another receptor – Nalbuphine, butorphanol • Agonist at the kappa receptor • Antagonist at the mu receptor • Antagonists - bind to opioid receptors but have no activity – naloxone, naltrexone
- 10. Odd Case - TramadolOdd Case - Tramadol • Works partially at the mu receptor – M1 metabolite • Works partially at the norepinephrine receptors • Additional unknown activity • Where does it fit?
- 11. Opioid Therapy: Routes ofOpioid Therapy: Routes of AdministrationAdministration • Oral and transdermal—preferred • Oral transmucosal—available for fentanyl and used for breakthrough pain • Rectal route—limited use • Parenteral—SQ and IV preferred and feasible for long-term therapy • Intraspinal—intrathecal over epidural generally preferred for long-term use
- 12. Metabolism of Codeine and MorphineMetabolism of Codeine and Morphine
- 13. Morphine MetabolismMorphine Metabolism • Morphine – Metabolized to M3G and M6G (normorpine) • Accumulates in renal failure and hepatic failure • M6G has potential nocioceptive activity • Significant polymorphism – Potent histamine release
- 14. MorphineMorphine • At a dose of 10mg per 70 kg body weight, gives relief in 70% of patients • Available in short and long acting formulations
- 15. NMDA ReceptorNMDA Receptor •Site of opioid tolerance •NMDA antagonists reduce the incidence of tolerance to morphine •Dexamathorphan •Methadone •Ketamine
- 16. Chemical Classes of OpioidsChemical Classes of Opioids • Phenylpiperidines – Fentanyl • Of all the opioids, has the least histamine mu-activity • Least allergenic – Meperidine • Only has a 2-3 hour duration • Metabolized to normeperidine – Renally excreted – Causes seizures, myoclonus – Not reversible by naloxone
- 19. Metabolism of FentanylMetabolism of Fentanyl • No active metabolites, low histamine release • Fentanyl is metabolized in the liver by to inactive metabolite – Macrolid antibiotics, antifungals, and protease inhibitors) may lead to increased blood levels • No first pass effect
- 20. Equianalgesic DosingEquianalgesic Dosing Drug Oral Dose IV Dose Duration morphine 30 mg 10 mg 3-4 hrs hydromorphone 4-8 mg 1.5 mg 3-4 hrs methadone 10-20 mg 6-12 hrs codeine 300 mg 150 mg 3-4 hrs oxycodone 20-30 mg 3-4 hrs hydrocodone 30 mg 3-4 hrs meperidine 300 mg 100 mg 2-3 hrs All doses are approximate, and vary between authors.
- 21. • CNS – Analgesia, chemical dependency – Sedation/drowsiness – Dizziness, mental clouding, depression, mood changes – Nausea, emesis (CTZ) – Antitussive (medullary cough center) – Disorientation, delirium, hallucinations, agitation, restlessness, nervousness, seizures Dose Related Opioid Side EffectsDose Related Opioid Side Effects
- 22. • Cardiovascular effects – Bradycardia (morphine, fentanyl) – Tachycardia (meperidine) – Cholinergic effects – Histamine release (fentanyl is the least) • Dermatologic effects – Diaphoresis, flushing, pruritis, urticaria • Genitourinary effects – Urinary retention, oliguria, vasopressin release Dose Related Opioid Side EffectsDose Related Opioid Side Effects
- 23. Dose Related Opioid Side EffectsDose Related Opioid Side Effects • Respiratory effects – CO2 tension response at the brainstem is decreased (decreased minute ventilation, rate, tidal volume) • Neuromuscular effects – Tremors (meperidine) – Rigidity (fentanyl) • Endocrine effects – Increased prolactin and growth hormone – Decreased LH, testosterone, thyrotropin release – Gonadotropin suppression (impotence), decreased libido
- 24. Dose Related Opioid Side EffectsDose Related Opioid Side Effects • Gastrointestinal effects – Xerostomia, decreased motility, increased sphinchter tone – Nausea, emesis (CTZ), orthostatic hypotension – Increased vestibular sensitivity
- 25. Anticipate and Manage SideAnticipate and Manage Side EffectsEffects • Constipation (opioid-induced bowel dysfunction) – Oral naloxone has been described – New agents such as methylnaltrexone and alvimopan
- 26. Anticipate and Manage SideAnticipate and Manage Side EffectsEffects • Nausea and emesis – Promethizine, compazine • Oral and rectal – Metaclopromide – Subligual droperidol • Itching – Not an allergic reaction – Reverses with low dose naloxone IV – Antihistamines – Reassure
- 27. Anticipate and Manage SideAnticipate and Manage Side EffectsEffects • Respiratory Depression – Clinically significant respiratory depression is rare when patients are in severe pain – Sedation precedes respiratory depression – Respiratory rate alone is not an indication of respiratory function – Use naloxone sparingly • Respiratory depression reverses before analgesia • Limit to doses of 100µg at a time • One amp (0.4mg) in 4cc NS, inject 1cc at a time • “You can always give more”
- 29. Opioid- Induced AndrogenOpioid- Induced Androgen DeficiencyDeficiency • Low serum levels of testosterone and: – Decreased libido – Erectile dysfunction – Fatigue – Depressed mood – Hot flashes • 70% of men on long term opioids have have subnormal testosterone levels
- 30. Opioid ResponsivenessOpioid Responsiveness • Opioid dose titration over time is critical to successful opioid therapy • Goal: Increase dose until pain relief is adequate or intolerable and unmanageable side effects occur • No maximal or “correct” dose • Responsiveness of an individual patient to a specific drug cannot be determined unless dose was increased to treatment-limiting toxicity
- 31. Poor Opioid ResponsivenessPoor Opioid Responsiveness • If dose escalation → adverse effects – Better side-effect management – Pharmacologic strategy to lower opioid requirement • Spinal route of administration • Add nonopioid or adjuvant analgesic – “Opioid rotation” – Nonpharmacologic strategy to lower opioid requirement
- 32. Opioid Therapy and ChemicalOpioid Therapy and Chemical DependencyDependency • Physical dependence • Tolerance • Addiction • Pseudoaddiction
- 33. Opioid Therapy and ChemicalOpioid Therapy and Chemical DependencyDependency • Physical dependence – Abstinence syndrome induced by administration of an antagonist or by dose reduction – Assumed to exist after dosing for a few days but actually highly variable – Usually unimportant if abstinence avoided – Does not independently cause addiction
- 34. Opioid Therapy and ChemicalOpioid Therapy and Chemical DependencyDependency • Tolerance – Diminished drug effect from drug exposure – Tolerance to side effects is desirable – Tolerance to analgesia is seldom a problem in the clinical setting • Tolerance rarely “drives” dose escalation • Tolerance does not cause addiction
- 35. Opioid Therapy and ChemicalOpioid Therapy and Chemical DependencyDependency • Addiction – Disease with pharmacologic, genetic, and psychosocial elements – Fundamental features • Loss of control • Compulsive use • Use despite harm – Diagnosed by observation of aberrant drug- related behavior
- 36. Opioid Therapy and ChemicalOpioid Therapy and Chemical DependencyDependency • Pseudoaddiction – Aberrant drug-related behaviors driven by desperation over uncontrolled pain – Reduced by improved pain control – Complexities • How aberrant can behavior be before it is inconsistent with pseudoaddiction? • Can addiction and pseudoaddiction coexist?
- 37. Opioid Therapy and ChemicalOpioid Therapy and Chemical DependencyDependency • Risk of addiction: Evolving view – Acute pain: Very unlikely – Cancer pain: Very unlikely – Chronic noncancer pain: • Surveys of patients without abuse or psychopathology show rare addiction • Surveys that include patients with abuse or psychopathology show mixed results
- 38. Opioid Therapy and ChemicalOpioid Therapy and Chemical DependencyDependency • Addressing aberrant drug-related behavior – Strategies to respond to aberrant behaviors • Frequent visits and small quantities • Long-acting drugs with no rescue doses • Use of one pharmacy, pill bottles, no replacements or early scripts • Use of urine screens • Coordination with sponsor, program, addiction medicine specialist, psychotherapist, others
- 39. Urine Drug Testing (UDT)Urine Drug Testing (UDT) • Oxycodone and methadone do not appear on standard UDTs – Gas chromatography-mas spectrometry • Codeine will appear as morphine • Heroin will appear as morphine Von Seggern RL et al. Headache 2004;44:4-47
- 40. State Specific DocumentationState Specific Documentation RequirementsRequirements • Arizona requires physicians to keep records such that they provide “sufficient information to allow another physician to assume care”. • Colorado suggests physicians use a written contract. • Mississippi requires physicians to keep patient records that include the presence of one or more recognized medical indications for the use of controlled substances. • Pennsylvania requires physicians to have a specific statement regarding patient symptoms, the diagnosis and the specific directions given for controlled substances Jennifer Bolen, The Legal Side of Pain
- 41. Opioid Therapy: ConclusionsOpioid Therapy: Conclusions • An approach with extraordinary promise and substantial risks • An approach with clear obligations on the part of prescribers – Assessment and reassessment – Skillful drug administration – Knowledge of addiction-medicine principles – Documentation and communication
- 43. A patient complains of inadequate analgesia and increases his use of his medication. This behavior may represent: A. Addiction B. Pseudoaddiction C. Tolerance D. All of the above Answer: D If the patient increases the medication despite the knowledge that he will be discharged, this may be addiction. If he increases the medication because of inadequate dosing, that may be pseudoaddiction. If he increases the medication because it is no longer effective, that may be tolerance.
- 44. Demerol (meperidine) should not be used for chronic pain because: A. it is addictive B. it is ineffective C. the metabolite causes seizures D. all of the above All opioids can potentially be abused. Meperidine may be useful for acute pain. The metabolite normeperidine can cause seizures and can accumulate with chronic dosing, especially in renal failure. Answer: C.
- 45. Strategies to reduce aberrant drug behaviors include: 1. Random urine drug screens 2. Narcotic contracts 3. No early refills 4. Opioid rotation Random drug screens, narcotic contracts, and aggressive refill policies have been felt to help control aberrant drug behaviors. Opioid rotation tries to address the issue of drug tolerance. Answer: A
- 46. 30mg of MSO4 orally is equivalent to: 1. 30mg MSO4 IV 2. 20mg of oral oxycodone 3. 30mg hydromorphone IV 4. 20mg methadone Answer: C Although equipotent charts may vary, in general, 30mg of oral MSO4 is equivalent to 10mg MSO4 IV, 20mg of oral oxycodone, 1.5mg of IV hydromorphone, or 20mg of methadone.
- 47. Receptors involved in opioid activity include: 1. Mu 2. Sigma 3. Kappa 4. Gamma Answer: A Mu, sigma, and kappa are opioid receptors. Gamma is not.
- 48. The most appropriate type of opioid for chronic pain might be an: A. Agonist B. Agonist/antagonist C. Antagonist D. Antihistamine Answer: A Mixed agonists/antagonists are poor choices for chronic pain treatment. Antagonists counteract the effect of opioids. Antihistamines are not opioids.
- 49. Patients usually develop tolerance to all opioid effects EXCEPT: A. Sedation B. Pruritis C. Constipation D. Pain relief Answer: C Sedation and pruritis (due to direct histamine release) abate over time. Although tolerance to pain relief can occur, with long acting narcotics (especially methadone) it is less likely. Constipation, however, should be expected to be a problem for the entire length of treatment.
- 50. Once an opioid treatment is selected, titration upwards should continue until: A. a ceiling is reached. B. addiction occurs C. tolerance occurs D. a balance between analgesia and side effects is reached. Answer: D There is no ceiling for opioids (other than the limitations of agonist/antagonists or APAP). The goal is to prevent addiction. Tolerance is less likely with long acting opioids. The goal is a balance between pain relief and intolerable side effects.
- 51. Examples of the phenanthrene class of opioid include all except: 1. Morphine 2. Fentanyl 3. Codeine 4. Meperidine Answer: B Morphine and codeine are phenanthrenes. Fentanyl and meperidine are phenylpiperidines.
- 52. If a patient is unable to tolerate oxycodone because of nausea, the least likely opioid to be tolerated would be: A. Fentanyl B. Propoxyphene C. Morphine D. Methadone Answer: C Morphine is in the same class of opioids (phenanthrenes) as oxycodone, but morphine has a 6- OH group (associated with more nausea). Fentanyl, propoxyphene, and methadone are completely different classes of opioids.
Editor's Notes
- Opioids may be delivered by numerous routes of administration. For long-term therapy, the oral and transdermal routes are preferred. The availability of the oral transmucosal formulation for fentanyl provided a novel method to treat breakthrough pain, one that appears to have a faster onset of effect than routine oral administration. Patients who cannot tolerate oral or transdermal therapy are sometimes candidates for long-term subcutaneous infusion. Intrathecal infusion via an implanted pump may be appropriate for patients who cannot tolerate the side effects associated with systemic therapy.
- For most patients, the goal during long-term therapy is to identify a favorable balance between analgesia and opioid side effects. The common side effects are constipation and mental clouding. Other side effects occur less often.
- Opioid responsiveness can be defined as the likelihood that a favorable balance between analgesia and side effects will be attained as the opioid dose is slowly titrated. A patient cannot be said to be a “nonresponder” unless the dose has been increased to the point of treatment-limiting side effects. Responsiveness varies with characteristics of a particular patient and his or her particular pain. Studies have suggested that responsiveness is inversely related to neuropathic mechanism, breakthrough pain, previous opioid exposure, cognitive impairment, and psychologic distress. However, no evidence exists that any characteristic imparts opioid resistance.
- Surveys in the cancer population suggest that 10% to 30% of patients will experience a poor response to an optimally titrated opioid regimen. Poorly-responsive patients can be considered for a variety of alternative opioid strategies. These include: 1) more sophisticated management of opioid side effects (eg, a psychostimulant for opioid-induced sedation or mental clouding), 2) use of a pharmacologic approach to reduce the systemic opioid requirement (either a trial of intraspinal therapy or coadministration of a nonopioid or adjuvant analgesic), 3) opioid rotation, or 4) a trial of a nonpharmacologic approach to reduce the opioid requirement (eg, a stimulatory, rehabilitative, anesthesiologic, surgical, or complementary approach). Comparative studies of these strategies have been conducted, and selection of one over another involves a detailed assessment, careful judgments about risks and benefits, and discussion of patient preferences.
- To optimize the use of opioid therapy, clinicians also must have familiarity with the principles of addiction medicine. This begins with an understanding of the definitions of physical dependence, tolerance, addiction, and pseudoaddiction.
- Physical dependence is defined solely by the occurrence of abstinence syndrome upon administration of an antagonist, cessation of therapy, or abrupt dose reduction. Physical dependence is expected, is not problematic as long as withdrawal is avoided, and differs from addiction. The words “addiction” or “addict” should never be used to describe the potential for withdrawal; the correct label in this situation is “physically dependent.”
- Tolerance is a complex process, defined as a reduction in a drug’s effect that is induced by exposure to the drug. Tolerance may be “associative,” due to learning, or “pharmacologic,” resulting from either pharmacodynamic or pharmacokinetic changes. In the case of analgesics, the term may apply to effects on pain or side effects. Based on clinical experience, pharmacodynamic tolerance to analgesia can result in declining efficacy. However, this appears to be an uncommon problem, because most patients’ doses stabilize for prolonged periods, and when dose escalation is needed, it typically occurs in the setting of worsening disease (and, therefore, cannot be called tolerance).
- Addiction is a disease with a strong neurobiologic component, which is defined by the behavioral phenomena of loss of control over drug use, compulsive use, and use despite harm. Clinicians who prescribe opioids must observe drug-related behaviors and attempt to determine whether or not these phenomena are occurring. In psychiatric parlance, the label addiction is not preferred, and the term “substance-dependence disorder” is used.
- The term “pseudoaddiction” was coined to describe the observation that some patients with cancer demonstrate aberrant drug-related behavior, which disappears when better analgesia is provided. Use of the term has expanded over time, and it is now used to refer to a broad range of problematic behaviors that appear to be related more to desperation than to craving. The phenomenon is complex, given the observation that pseudoaddiction and addiction can coexist.
- If the definition of addiction is clear, the question can be asked: What is the risk for iatrogenic addiction in patients without a known history of addiction during opioid treatment for pain? The literature suggests that the risk is minor during the treatment of acute pain and chronic cancer pain (possibly because cancer is a disease of older patients and those who have the disease and no history of drug abuse probably lack the biologic predisposition to addiction). The literature pertaining to chronic nonmalignant pain cannot adequately clarify this question. The probability of addiction, overall, presumably is small but likely to be influenced by a number of predictors. These predictors have not yet been empirically established; based on clinical experience, they may include a personal history of substance abuse, family history of substance abuse, age, personality factors, family dynamics, and social factors.
- From the clinical perspective, an initial assessment for the occurrence of aberrant drug-related behavior is needed. This may require a variety of strategies, including communication with the pharmacy or with others, urine drug screening, or specific rules governing prescription acquisition or follow-up. If aberrant drug-related behaviors are occurring, the assessment must be broad enough to determine whether they reflect the development of an addictive disorder or some other problem. This latter point highlights the certainty that not all aberrant drug-related behavior is addiction.
- If patients do engage in aberrant drug-related behaviors, management may take any number of turns and should be based on knowledge of the appropriate laws and regulations and diagnostic considerations.
- In some cases, a patient engaged in aberrant drug-related behavior should discontinue therapy. Pain can be treated in other ways, or the patient can be appropriately referred. In some cases, referral for addiction treatment is appropriate. If the decision is made to continue opioid therapy, the behaviors should be controlled using one or more strategies. These strategies may include frequent visits, small refills, checking of pill bottles, the use of long-acting drugs without rescue doses, the requirement that only one pharmacy be used, the use of spot urine toxicologies (to determine whether other drugs of abuse are being taken), and the requirement for visits with a sponsor or mental health care provider. In some cases, the use of a written “contract” is a useful intervention. It should stipulate guidelines for therapy and also indicate the consequences of further aberrant drug-related behavior.
- Long-term opioid therapy is an extremely valuable approach to the treatment of chronic pain. Clinicians who manage this therapy must be able to perform a careful assessment and reassessment, administer these drugs knowledgeably, monitor outcomes (including the potential for aberrant drug-related behavior), and address negative outcomes. Documentation of multiple outcomes is essential.