Opioids – general pharmacology

Medications

• Buprenorphine
• Codeine
• Fentanyl
• Hydromorphone
• Methadone
• Morphine
• Oxycodone
• Tapentadol
• Tramadol

Evidence for Use of Opioids for Chronic Non-Cancer Pain (CNCP)

• Acute Pain: Strong evidence from RCTs supports opioid efficacy.
• Cancer Pain, Palliative Care, and Opioid Dependence: Supported by systematic reviews.
• CNCP: A group of entities with various and evolving aetiologies, requiring careful interpretation of evidence and clinical practice translation.

Evidence in Different Chronic Pain Conditions

Musculoskeletal Pain

• General Practice: A large proportion of opioid prescriptions are for musculoskeletal conditions.
• Osteoarthritis:
  • Fair evidence for tramadol.
  • Limited evidence for transdermal buprenorphine, shown to be effective and well-tolerated.
  • Limited evidence for tapentadol.
• Chronic Low Back Pain:
  • Some support for short-term use; evidence beyond three months is lacking.
  • Limited evidence for transdermal buprenorphine, tapentadol, and tramadol/paracetamol combinations for at least 12 weeks’ duration.
• Long-Term Use Caution: Only 25% of patients benefit from sustained opioid effects; harms include abuse and mortality.

Neuropathic Pain

• Guidelines: Opioids are not recommended as first-line treatment.
• Second-line or Third-line Treatment:
  • Tramadol: Weak GRADE recommendations; considered second-line due to safety and tolerability (NNT for 50% pain reduction is approximately 5).
  • Strong Opioids (Oxycodone and Morphine): Weak GRADE recommendations; considered third-line due to safety concerns (NNT for 50% pain reduction is approximately 4).
  • Some reviews are less favorable for oxycodone (NNT at 5.7 for moderate benefit).
• Comparative Efficacy: NNT for opioids similar to other drugs (antidepressants, anticonvulsants) used in painful neuropathies.
• Combination Therapies: Modest superiority of gabapentin plus opioid versus gabapentin alone, but with more dropouts due to side effects.

challenge of putting evidence into practice

Translating Evidence to Practice

• Complexity of Pain: Pain is subjective and influenced by numerous factors, making it difficult to generalize trial results.
• Diverse Conditions: CNCP includes various conditions with different aetiologies, requiring tailored therapeutic approaches.
• Individual Variability: Patients with the same condition can have unique pain experiences and varied responses to treatments.

Efficacy of Analgesics

• Limited Universal Efficacy: No single analgesic works well for all patients; most provide significant relief to a small subset.
• Placebo Effect: Strong placebo effects often influence pain relief outcomes.
• Bimodal Response Distribution: Pain relief is typically either very good or poor, making average response data misleading.

Clinical Trials vs. Real-World Practice

• Trial Design Issues: Regulatory trials use single interventions and fixed doses, often leading to higher adverse events and withdrawal rates.
  • High failure rates for NSAIDs in osteoarthritis (≥70%), chronic low back pain (≥80%), and ankylosing spondylitis (58–72%).
  • High failure rates for antidepressants and anticonvulsants in neuropathic pain conditions.
• Responder Analysis: Cochrane Pain, Palliative, and Supportive Care Systematic Review Group recommends measuring the proportion of patients achieving significant pain reduction (30–50%).

Implications for Clinical Practice

• Individualized Treatment: Focus on individual responses to therapy, trialing multiple options to find effective relief.
• Responder vs. Non-Responder: Non-responders should discontinue ineffective treatments.
• Importance of Responder Analysis: Changes judgement of benefit and risk, suggesting classical trials using averages may underestimate efficacy.

Specific Treatment Considerations

• Failure of Common Analgesics: Paracetamol and NSAIDs show limited efficacy in musculoskeletal pain; opioids, anticonvulsants, and antidepressants often underperform in neuropathic pain.
• Clinical Judgement: Evidence from single interventions should be integrated with individual patient circumstances, tempered by clinical experience.

Opioids – Mode of Action

• Receptor Interaction: Opioids act as pure or partial agonists on opioid receptors in the central and peripheral nervous systems.
• Receptor Types: There are three main types of opioid receptors: mu (µ), kappa (κ), and delta (δ).
• Effects: Action at receptors produces a range of effects including:
  • Analgesia (primarily due to mu receptor agonism)
  • Respiratory depression
  • Cough suppression
  • Euphoria
  • Sedation
  • Decreased gastrointestinal motility (leading to constipation)
  • Physical dependence

Metabolism and Duration of Activity

• Individual Variability: Response to opioids varies due to factors such as age, gender, and genetic differences.
• Age: Age is a better determinant than weight for opioid requirements, mainly due to differences in brain penetration pharmacodynamics.
• Gender: Gender influences opioid response, potentially due to interactions between estrogen and opioid receptors.
• Genetics: Genetic differences affect opioid pharmacokinetics and pharmacodynamics, leading to variability in opioid therapy response.
  • Ultrarapid metabolizers (carriers of CYP2D6 gene duplication) have higher levels of morphine metabolites after codeine/tramadol administration, increasing risk of respiratory depression and death.
  • Poor metabolizers experience more severe postoperative pain.

Specific Opioids and Their Indications

• 2020 TGA-Approved Indications: Indications are aligned across the class, divided into immediate-release and modified-release categories, except for fentanyl patches.
  • Immediate-Release Products: Indicated for short-term management of severe pain when other treatments have failed, are contraindicated, not tolerated, or inappropriate.
  • Modified-Release Products: Indicated for long-term management of severe pain under specific conditions, not for use in chronic non-cancer pain except in exceptional circumstances.
  • Fentanyl Patches: Indicated for cancer-related pain, palliative care, and other conditions in opioid-tolerant patients; not for use in opioid-naïve patients.

Opioid Formulations and Doses

Formulations

• The practical usefulness of opioids is related to the available formulations.

Approximate Equivalence Doses

• Oral Morphine: The standard against which other opioids are measured.
• Equianalgesic Doses: Full opioid agonists given in equianalgesic doses produce the same analgesic effect.
  • Variability: Accurate determination of equianalgesic doses is difficult due to individual variability in pharmacokinetics and dynamics.
  • Conversion Caution: Converting to methadone requires special caution; start at low doses and consult national guidelines or specialists.

Useful Tools for Calculating Equivalent Doses

• ANZCA Opioid Calculator App: Created by the Faculty of Pain Medicine at the Australian and New Zealand College of Anaesthetists.
• GP Pain Help App and Website: Developed by the Centre for Palliative Care Research and Education.

Opioid Ceiling Doses

• Caution: Use caution when prescribing opioids at any dosage; aim for the lowest effective dose.
• Reassessment: Carefully reassess when increasing dosage to 50 mg oral morphine equivalent (OME) or more per day.
• Specialist Involvement: Justify titrating to 100 mg or more OME per day and avoid doing so without specialist involvement.

Tolerance and Opioid-Induced Hyperalgesia (OIH)

Tolerance

• Definition: A predictable state of adaptation where exposure to a drug induces changes that result in a reduction of one or more of the drug’s effects over time.
• Mechanism: The patient becomes desensitized to the drug, necessitating increased doses to achieve the same effect.
• Types of Tolerance:
  • Pharmacological Tolerance: Predictable and physiological decrease in the effect of a drug over time.
  • Apparent Tolerance: Occurs when both tolerance and OIH contribute to decreased opioid effectiveness.

Opioid-Induced Hyperalgesia (OIH)

• Definition: Sensitization of pro-nociceptive pathways leading to pain hypersensitivity due to opioid administration.
• Mechanism: Results in a decrease in the analgesic effect of opioids, reducing their efficacy over time.

Differences Among Opioids

• Methadone and Fentanyl: Less likely to lose effect over time due to promotion of opioid receptor internalization and receptor recycling.
• Morphine: Leads to little or no receptor internalization, increasing the risk of developing tolerance.

Clinical Implications

• Pain Management: In cases of decreased effectiveness of opioid therapy, it can be challenging to determine whether tolerance or OIH is the cause.
  • Tolerance: Inadequate pain relief may improve with opioid dose escalation.
  • OIH: Pain control may improve with a reduction in opioid dose.
• Recommended Action: Reduce opioid doses when faced with decreased effectiveness to differentiate between tolerance and OIH.

Tolerance to Adverse Effects

• Rapid Tolerance: Develops to sedation, cognitive effects, nausea, and respiratory depression.
• Little Change: Tolerance does not significantly affect miosis or constipation.

Summary

• Management Dilemma: Distinguishing between tolerance and OIH is crucial but challenging in clinical practice.
• Dose Adjustment: Careful dose adjustment and monitoring are essential to optimize pain management and minimize adverse effects.
• Opioid Selection: Consider the varying likelihood of tolerance and OIH among different opioids when choosing a treatment regimen.

Dependence and Withdrawal

Definition of Dependence

• Pharmacological Terms: Dependence is a time-limited state that develops during chronic drug treatment.
• Abstinence Reaction: Cessation of the drug elicits withdrawal symptoms, which are reversed by renewed administration of the drug.

Opioid Withdrawal Syndrome

• Characterization: Signs and symptoms of sympathetic stimulation due to decreased sympathetic antagonism by opioids.
• Symptom Onset: Symptoms start two to three half-lives after the last dose of opioid.
  • Example: Oxycodone has a half-life of 3–4 hours, so symptoms start after 6–12 hours, peak at approximately 48–72 hours, and resolve within 7–14 days.
• Variability: Timelines and symptoms vary depending on the duration of action, specific dose, speed of taper, and duration of use.

Minimizing Withdrawal

• Gradual Reduction: Withdrawal can be minimized by gradually reducing opioid use.
• Non-Life Threatening: Withdrawal is not life-threatening unless the patient has significant comorbidity or is medically unstable, but it can be very distressing.

Management of Acute Withdrawal

• Acute Withdrawal: Occurs when opioids are stopped suddenly or an antagonist (e.g., naloxone, naltrexone) is administered.
• Treatment:
  • Reintroduce Opioids: Gradually reintroduce opioids.
  • IV Fluids, Glucose, Adrenergic Blocking Drugs: Provide supportive care with these treatments.
  • Clonidine: Useful to manage symptoms.
  • Reassurance and Comfort Measures: Provide emotional support and comfort to the patient.

Summary

• Dependence: A predictable state that can lead to withdrawal symptoms upon cessation.
• Withdrawal Symptoms: Managed through gradual tapering, supportive care, and, if necessary, reintroduction of opioids.
• Acute Withdrawal: Requires prompt medical management to alleviate symptoms and ensure patient comfort.

Harms Associated with Opioids

• Common Adverse Effects: Sedation, pruritus, nausea, vomiting, slowing of gastrointestinal function, and urinary retention.
• Uncommon Adverse Effects: Prolonged QT-interval with risk of Torsades de Pointes (TdP) and cardiac arrest (associated with methadone and oxycodone).
• Dose-Related Effects: Adverse effects are typically dose-related.

Summary

• Formulations: Opioids are available in various formulations to cater to different clinical needs.
• Equianalgesic Doses: Aim to use standardized tools and guidelines to determine equivalent doses, with caution in specific cases like methadone conversion.
• Ceiling Doses: Aim for the lowest effective dose and involve specialists for higher dosages.
• Tolerance and OIH: Be aware of tolerance and OIH when managing long-term opioid therapy.
• Dependence and Withdrawal: Manage withdrawal carefully to minimize patient distress and potential harm.
• Adverse Effects: Monitor and manage common and uncommon adverse effects to ensure patient safety.

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Buprenorphine

Mechanism of Action

• Receptor Interaction: Partial agonist at mu opioid receptors and antagonist at delta and kappa receptors.
• Forms: Used for analgesia in low-dose patch formulations and in opioid replacement therapy (ORT) with oral and sublingual formulations.

Musculoskeletal Pain

• Chronic Non-Cancer Pain (CNCP): Limited evidence due to a lack of high-quality randomized controlled trials (RCTs).
• Osteoarthritis: Transdermal buprenorphine shown to be effective and well-tolerated, with analgesic effects similar to tramadol.

Neuropathic Pain

• Effectiveness: Case reports suggest effectiveness in peripheral and central neuropathic pain.
• Evidence: Lack of large trials; current evidence insufficient to support or dispute efficacy in neuropathic pain conditions.

Addiction Medicine

• Opioid Replacement Therapy (ORT): Listed for use under Section 100 (S100).

Practical Use

• PBS Listing: Listed for chronic severe pain and ORT.
• Transdermal Patches: Generally provide a week of analgesia; may need more frequent changes if drug release decreases.

Safety and Tolerability

• Renal Impairment: Safe for use; less immunosuppressive than pure mu opioid agonists.
• Respiratory Depression: Lower risk compared to morphine, methadone, hydromorphone, and fentanyl; has a ceiling effect.
• Reversal: Respiratory depression can be reversed with naloxone; higher doses and longer infusion may be required.
• Withdrawal Symptoms: Milder and more delayed in onset compared to other opioids.

Drug Interactions

• Mu Receptor Binding: Strong binding without full activation; may cause interactions with pure mu agonists.
• Maintenance Therapy: Pure mu agonists may be less effective in patients on maintenance buprenorphine.
• Precipitated Withdrawal: Theoretically possible if buprenorphine is given to patients on long-term opioid therapy but usually only at higher doses used for ORT.

Summary

• Buprenorphine is an effective option for certain pain conditions and ORT with a favorable safety profile.
• Requires careful management to avoid interactions and withdrawal symptoms.
• Offers significant benefits in terms of lower respiratory depression risk and suitability for patients with renal impairment.

Codeine

Mechanism of Action

• Receptor Interaction: Weak mu receptor agonist with 200-fold weaker affinity than morphine.
• Metabolism: Analgesic action depends on the metabolism to morphine (about 10% of the dose) via CYP2D6.
  • Ultrarapid Metabolizers: Experience higher levels of morphine and metabolites, increasing risk of respiratory depression and death.
  • Poor Metabolizers: Do not produce morphine and therefore gain no analgesic effect.

Misuse and Dependence

• Misuse Rates: Average between 21% and 29%.
• Dependence Rates: Average between 8% and 12%.
• Overdose: Most common prescription opioid associated with fatal overdoses in Victoria.

Musculoskeletal Pain

• Combination Use: Commonly combined with other minor analgesics (e.g., paracetamol, ibuprofen).
• Effectiveness: High-quality evidence supports combination codeine medicines for clinically important pain relief in the immediate term, mostly in acute pain.

Practical Use

• Classification: Weak opioid.
• PBS Listing: Listed for severe pain; no role in chronic pain management.
• Dosage and Efficacy:
  • A single 60 mg dose provides good analgesia for a few adults; 12 patients need to be treated for one to achieve a 50% reduction in postoperative pain.
  • Preparations with low doses (8–15 mg codeine phosphate) are considered sub-therapeutic.
  • Combining codeine with non-opioid analgesics provides limited additional benefit; seven patients need to be treated with ibuprofen 400 mg/codeine 25.6–60 mg for one to achieve at least a 50% reduction in postoperative pain compared to ibuprofen 400 mg alone.

Monitoring and Safety

• Response Variability: Due to genetic differences in metabolism.
• Risk of Harm: Close monitoring is necessary due to the variability in response and potential for misuse and dependence.

Summary

• Codeine is a weak opioid used primarily for acute pain management, often in combination with other analgesics.
• Its efficacy and risk of adverse effects vary significantly due to genetic differences in metabolism.
• While useful for certain pain conditions, it requires careful monitoring to prevent misuse, dependence, and overdose.

Fentanyl

Mechanism of Action

• Receptor Interaction: Highly potent opioid active at the mu receptor.
• Metabolism: Metabolized almost exclusively in the liver to minimally active metabolites.
  • Renal Excretion: Less than 10% of unmetabolized fentanyl is excreted renally, making it useful in renal failure.

Formulations and Indications

• Transdermal Patches: Suitable for long-term cancer pain treatment.
• Oral Transmucosal Lozenges or Lollipops: Used to treat breakthrough pain in cancer patients who are not opioid-naïve.
• Injectable Preparations: Available for various medical uses.
• Equivalence: A 25 µg/hour fentanyl patch is approximately equivalent to 90 mg of oral morphine per day.

Safety and Misuse

• Fentanyl-Related Mortality: Relatively low in Australia compared to the US and parts of Europe, but misuse is rising.
• At-Risk Groups: High misuse potential among groups who inject drugs; known for high street value and diversion potential.
• Indications for Use: Should be used only as indicated, primarily for cancer pain when other options are exhausted.

Practical Use

• PBS Listing: Listed for chronic, severe, disabling pain, usually in cancer care or acute hospital settings.
• Opioid-Naïve Patients: Not suitable as the initial agent for pain management due to high morphine-equivalent doses and significant risk of toxicity and overdose.
• Heat Sensitivity: Local heat (e.g., hydrotherapy pools) may increase absorption from transdermal patches, requiring caution.

Summary

• Fentanyl is a highly potent opioid suitable for specific pain management scenarios, especially in cancer patients.
• Its use should be carefully monitored to prevent misuse and manage risks, especially in opioid-naïve patients.
• The transdermal patch offers a convenient option for long-term pain management but requires careful handling to avoid increased absorption and overdose risks.

Hydromorphone

Mechanism of Action

• Receptor Interaction: Strong opioid acting as a mu receptor agonist.
• Potency: Approximately five times as potent as morphine.
• Analgesic Effect: Provides slightly better clinical analgesia than morphine.

Metabolism and Excretion

• Main Metabolite: Hydromorphone-3-glucuronide (H3G).
• Excretion: Dependent on the kidneys.
• Neurotoxic Effects: H3G has no analgesic action but can lead to dose-dependent neurotoxic effects.

Formulations

• Available Forms: Solution for injection, oral liquid, and tablets.
• Misuse Potential: Extremely high potential for misuse and high street value.

Practical Use

• PBS Listing: Listed for chronic, severe, disabling pain.
• Usual Practice: Typically restricted to malignant pain or patients undergoing dialysis.
• Opioid-Naïve Patients: Not suitable as the initial agent in pain management for opioid-naïve patients.

Summary

• Hydromorphone is a potent opioid with significant analgesic effects, used primarily for severe pain management in specific patient groups.
• It requires careful monitoring due to its high potential for misuse and associated neurotoxic effects from its metabolite.
• Its use is typically limited to malignant pain and dialysis patients, avoiding use in opioid-naïve individuals.

Methadone

Mechanism of Action

• Receptor Interaction: Agonist at the mu receptor and antagonist at the N-methyl-D-aspartate (NMDA) receptor.
• Uses: Commonly used for maintenance treatment of opioid addiction and chronic pain management.

Pharmacokinetics

• Oral Bioavailability: Good (70-80%).
• Potency: High potency with a long duration of action.
• Metabolites: No active metabolites.
• Half-Life: Long and unpredictable (mean of 22 hours; range 4-190 hours), increasing risk of accumulation.

Drug Interactions

• P450 Enzyme System: Significant effects with concurrent administration of other drugs metabolized by this system.
  • P450 Inducers: (e.g., carbamazepine, rifampicin, phenytoin, St John’s wort, some antiretroviral agents) can increase methadone metabolism, lowering blood levels and potentially causing reduced efficacy or withdrawal.
  • P450 Inhibitors: (e.g., other antiretroviral agents, some selective serotonin reuptake inhibitors [SSRIs], grapefruit juice, antifungal agents) can raise methadone levels, increasing the risk of adverse effects or overdose.
• Drug Interaction Check: Can be done online.

Practical Use

• PBS Listing: Listed for chronic, severe, disabling pain and opioid replacement therapy (ORT) as Section 100 (S100).
• Formulations:
  • Methadone Liquid: Used once daily for maintenance in opioid-dependent patients.
  • Methadone Tablets: Typically used three to four times daily for managing persistent pain.
• Specialist Use: Usually confined to specialist pain medicine areas due to complicated and unpredictable pharmacokinetics.
• Caution in Dosing: Extreme caution required when initiating methadone. Slow titration and close monitoring are necessary.
  • Steady State: May take up to two weeks to reach steady state levels.
  • Risk of Accumulation: Rapid dose increases can lead to excessive sedation, high risk of overdose, and death.

Summary

• Methadone is a versatile synthetic opioid used in addiction treatment and chronic pain management.
• It has complex pharmacokinetics requiring careful monitoring and cautious dose titration.
• Drug interactions via the P450 enzyme system are significant and must be managed to avoid adverse effects.

Morphine

Mechanism of Action

• Receptor Interaction: Widely used opioid agonist at the mu receptor.
• Standard: Considered the standard against which other opioids are compared.

Metabolism and Excretion

• Main Metabolites:
  • Morphine-6-glucuronide (M6G): Mu opioid receptor agonist and main mediator of analgesia.
  • Morphine-3-glucuronide (M3G): Low affinity for opioid receptors, no analgesic activity, associated with neurotoxic symptoms (hyperalgesia, allodynia, myoclonus).
• Renal Elimination: Both metabolites are eliminated renally.

Risk Factors

• Higher Risk of Adverse Effects:
  • Higher doses, older age, impaired renal function, and oral administration (due to first-pass metabolism) can lead to higher concentrations of M3G and M6G.
  • Potential for severe, long-lasting sedation and respiratory depression.
• Immunosuppressive: Morphine is the most immunosuppressive of the available opioids, although the clinical significance is uncertain.

Trends and Usage

• Decrease in Prescribing: Morphine prescriptions have decreased in Australia.
• Prevalence: Prescriptions are most prevalent among older Australians.

Pain Management

• Musculoskeletal Pain: Evidence for managing chronic non-cancer pain (CNCP), including low back pain, is poor.
• Neuropathic Pain: Weak GRADE recommendations for use; recommended as third-line mainly due to safety concerns.

Practical Use

• PBS Indications: Indicated for severe disabling pain (cancer, palliative care) and chronic severe pain.
• Commencement Doses: Vary according to patient selection and age.

Summary

• Morphine remains a widely used opioid for acute, persistent, and cancer pain, serving as the standard for comparison.
• Its metabolites have differing effects, with M6G providing analgesia and M3G associated with neurotoxic symptoms.
• Renal function and patient age are critical considerations due to the risk of accumulation and adverse effects.
• Usage has decreased, with prescriptions most common among older adults.
• Morphine’s role in chronic non-cancer and neuropathic pain is limited by safety concerns and weaker evidence of efficacy.

Oxycodone

Mechanism of Action

• Receptor Interaction: Primarily mediated by mu receptor agonism.
• Metabolites: Noroxycodone and oxymorphone (via CYP3A4) are weakly active.
• CYP2D6 Activity: Oxycodone concentration and effect may depend on CYP2D6 activity:
  • Ultrarapid Metabolizers: Experience better analgesic effects but higher toxicity.
  • Poor Metabolizers: Experience reduced analgesic effects.

Pharmacokinetics and Usage

• Postoperative Pain: CYP2D6 genotype does not appear to influence oxycodone requirements in acute postoperative pain.
• Popularity: Increasing use in acute, hospital, and perioperative settings due to:
  • Faster onset of action than morphine.
  • Better oral bioavailability.
  • Longer duration of action.
  • Fewer concerns about metabolites.
  • Lower rate of adverse effects.

Safety and Misuse

• Oxycodone-Related Deaths: Relatively low in Australia compared to the US.
• Addiction: Increasing use and high potential for misuse; popular in both medical and non-medical settings.

Pain Management

• Musculoskeletal Pain: Poor evidence for managing chronic non-cancer pain (CNCP).
• Neuropathic Pain: Weak GRADE recommendations for use; recommended as third-line due to safety concerns.

Practical Use

• PBS Listing: Indicated for severe disabling pain and chronic severe pain.
• Hospital and Acute Pain Settings: Popular for its favorable pharmacological properties.
• Rehabilitation Settings: Care should be taken to minimize chronic use.
• Community Prescribing Post-Discharge: GPs should wean patients off opioid analgesics post discharge.
• Combination with Naloxone: Available to reduce constipation, though risks of misuse and diversion still exist.

Drug Interactions

• St John’s Wort (Hypericum perforatum): Induces metabolism of oxycodone, significantly reducing its plasma concentrations and efficacy.

Summary

• Oxycodone is a potent opioid with advantageous pharmacokinetic properties, making it popular in acute and hospital settings.
• Its use in chronic non-cancer and neuropathic pain is limited by safety concerns and weaker evidence of efficacy.
• Careful monitoring and management are necessary to prevent misuse and ensure safe post-discharge use.

Tapentadol

Mechanism of Action

• Receptor Interaction: Combined weak mu agonist and noradrenaline reuptake inhibitor.
• Active Metabolites: None.

Efficacy and Adverse Effects

• Chronic Pain Conditions: Shows comparable or better efficacy than conventional opioids.
• Gastrointestinal Adverse Effects: Reduced rates of nausea, vomiting, and constipation compared to conventional opioids, resulting in less treatment discontinuation.

Cardiovascular Effects

• Heart Rate and Blood Pressure: No effect on heart rate or blood pressure up to the maximum recommended dose of 500 mg/day, even in patients with hypertension and/or on antihypertensives.

Metabolism and Dose Adjustment

• Liver Metabolism: Metabolized by the liver; impaired hepatic function may require dose adjustment.

Safety and Misuse

• Overdose Deaths: Only two reported cases of overdose death despite widespread use in the US and Europe.
• Misuse and Diversion: Lower rate of misuse and diversion compared to oxycodone and hydrocodone, similar to tramadol.

Pain Management

• Cancer Pain: Limited data to support a role for tapentadol in cancer pain.

Practical Use

• Chronic Pain: Effective for various chronic pain conditions with a favorable safety profile.
• Controlled Medicine: Subject to control in all countries but shows a lower rate of misuse and diversion.

Summary

• Tapentadol is an effective pain management option with dual action as a weak mu agonist and noradrenaline reuptake inhibitor.
• It offers a better safety profile, especially concerning gastrointestinal side effects, making it a suitable alternative to conventional opioids.
• Careful monitoring and dose adjustment are required in patients with impaired hepatic function.
• Its lower potential for misuse and diversion, along with a minimal impact on cardiovascular parameters, makes it a valuable option in chronic pain management.

Tramadol

Mechanism of Action

• Receptor Interaction: Acts as both a weak opioid agonist and a serotonin and noradrenaline reuptake inhibitor.
• Metabolite: Metabolized by CYP2D6 to an active metabolite, O-desmethyltramadol (M1), which is a more potent mu opioid receptor agonist.
• Metabolism Impact: Poor metabolizers receive less analgesic effect due to reduced formation of M1.

Adverse-Effect Profile

• Common Side Effects: Nausea and vomiting, occurring at rates similar to morphine.
• Gastrointestinal Effects: Less impact on gastrointestinal motor function than morphine.
• Respiratory Depression: Causes less respiratory depression than other opioids at equianalgesic doses.
• Seizure Risk: Does not increase the incidence of seizures compared with other analgesic agents.
• Serotonin Toxicity: Risk of inducing serotonin toxicity when combined with other serotonergic medicines, especially SSRIs.

Misuse Potential

• Lower Misuse Potential: Lower potential for misuse compared to conventional opioids.

Pain Management

• Musculoskeletal Pain: Fair evidence for managing osteoarthritis.
• Neuropathic Pain: Weak GRADE recommendation for use; generally considered second line due to tolerability and safety concerns.

Practical Use

• PBS Listing: Listed for acute or chronic, severe pain not responding to aspirin and/or paracetamol and for the short-term treatment of acute, severe pain.
• Tolerance and Side Effects: Side effects often limit use, but it can be useful if tolerated.

Summary

• Tramadol is an atypical centrally acting analgesic with combined weak opioid agonist and serotonin/noradrenaline reuptake inhibitor effects.
• It provides a different side effect profile, with less gastrointestinal impact and respiratory depression than other opioids.
• Its metabolism via CYP2D6 affects its efficacy, particularly in poor metabolizers.
• While it has a lower potential for misuse, its use is often limited by side effects, but it remains a valuable option in certain pain management scenarios.