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.
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.
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.
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.
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.