Pain – Adjuvant medications

Caffeine

• Usage: Added to common analgesics (paracetamol, ibuprofen, aspirin).
• Effectiveness:
  • Small but statistically significant benefit with a dose of 100–130 mg.
  • Benefit is consistent across different pain conditions and types of analgesics.
• Safety:
  • No serious adverse events reported.
  • Safe if the recommended dose is not exceeded.

Antidepressants

General Considerations

• Withdrawal:
  • All classes associated with withdrawal syndromes.
  • Taper slowly if discontinuing the drug.
• Misuse/Abuse:
  • Rare, mostly in individuals with comorbid substance use and mood disorders.

Tricyclic Antidepressants (TCAs)

Musculoskeletal Pain

• Chronic Low Back Pain: No significant difference between TCAs and placebo.

Neuropathic Pain

• General Efficacy:
  • Considered first-line or second-line therapies.
  • Guideline recommendations differ; varied quality of supportive data.
  • Recent analyses report modest efficacy and weak evidence due to bias and large placebo responses.
• Specific Conditions:
  • Cancer/HIV-associated neuropathic pain: Refractory to TCAs.
  • Analgesic combinations: Supported in selected neuropathic pain conditions.
• In Practice:
  • Amitriptyline: Effective for some with neuropathic pain or fibromyalgia (NNT 4.9).
  • Dosing: Start at 5–10 mg at night, assess for benefit/harm after one week, increase slowly to max 75–100 mg.
  • Older Patients: Use caution due to anticholinergic activity risks (cognitive impairment, falls, mortality).

Fibromyalgia

• Most Effective TCA: Amitriptyline (NNT 4.9).

Serotonin Noradrenaline Reuptake Inhibitors (SNRIs)

Musculoskeletal Pain

• Osteoarthritis:
  • Duloxetine recommended.
  • As effective as other first-line treatments (e.g., NSAIDs).
  • Well-tolerated in older patients with knee osteoarthritis pain.

Neuropathic Pain

• General Efficacy:
  • Duloxetine and venlafaxine effective first-line treatments.
  • Duloxetine safe and effective for older patients with diabetic peripheral neuropathy.
• Specific Conditions:
  • Chemotherapy-Induced Peripheral Neuropathy (CIPN):
    • Duloxetine (30 mg titrated to 60 mg/day) modestly reduces pain severity.
    • Additional benefits: Reduced numbness, tingling, improved quality of life.
• In Practice:
  • Start duloxetine at 30 mg, assess weekly, increase dose if partial pain relief is achieved.
  • Duloxetine 60–120 mg/day provides analgesia for diabetic neuropathy, lower efficacy for fibromyalgia.
  • Minimize adverse effects; common side effect: intolerable drowsiness.

Fibromyalgia

• Duloxetine:
  • Reduces pain and improves quality of life (NNT ~6).
  • Not effective for improving sleep or fatigue.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Effectiveness: Limited evidence for effectiveness in neuropathic pain.

Anticonvulsants

Alpha-2-Delta Ligands (Gabapentin and Pregabalin)

Neuropathic Pain

• General Efficacy:
  • Recommended for chronic neuropathic pain (e.g., diabetic polyneuropathy, post-herpetic neuralgia).
  • Evidence varied in general practice settings.
  • Some analyses found significant benefit; others highlight high risk of adverse events and weak evidence.
• Specific Conditions:
  • Effective in relieving pain from traumatic/post-surgical nerve injury.
• In Practice:
  • First-line for chronic neuropathic pain (NNT 4–10, sometimes greater than 10).
  • Start pregabalin at 25 mg at night/twice daily, assess weekly, increase dose if partial relief is achieved.
  • Monitor for benefit within the first two weeks; discontinue if no meaningful benefit.
  • Common side effect: drowsiness.
  • Evaluate for SUDs; monitor for problematic use, assist in tapering off if necessary.

Fibromyalgia

• Effectiveness: Gabapentin and pregabalin effective in relieving pain.

Carbamazepine

• Effectiveness:
  • First-line for trigeminal neuralgia; supported by good evidence.
  • Less strong evidence for other chronic neuropathic pain.

Valproate

• Effectiveness:
  • May reduce pain in diabetic polyneuropathy based on small, poor-quality RCTs.
  • Lacks strong evidence support.

Lamotrigine

• Effectiveness: No analgesic benefit in large, high-quality RCTs.

Naloxone (Low-Dose )

Naloxone, traditionally known as an opioid antagonist used to reverse opioid overdose, has been explored in low doses as an adjunct in pain management. The rationale is that low-dose naloxone can potentially mitigate some of the adverse effects of opioid therapy, such as opioid-induced hyperalgesia and tolerance, without reversing the analgesic effects of opioids.

1. Opioid-Induced Hyperalgesia (OIH):
   • Studies suggest that low-dose naloxone can reduce OIH. OIH is a condition where patients receiving opioids for pain management paradoxically experience increased sensitivity to certain painful stimuli.
   • Low-dose naloxone can attenuate this effect, improving pain management outcomes.
2. Reduction of Opioid Tolerance:
   • Low-dose naloxone may help in reducing the development of tolerance to opioids. Tolerance is a state where increasing doses of opioids are required to achieve the same analgesic effect, potentially leading to higher doses and increased side effects.
   • By reducing tolerance, naloxone can help maintain the efficacy of opioids at lower doses.

Dosing

• Typical Low Doses: The doses of naloxone used in studies vary, but they are generally much lower than those used to reverse opioid overdose.
  • Range: 0.25 to 2 micrograms per kilogram per hour (µg/kg/hr).
  • Administration: Often administered intravenously as a continuous infusion in a hospital setting.

Follow-Up and Monitoring

• Initial Assessment: Patients should be closely monitored initially to ensure that naloxone does not reverse the analgesic effects of opioids.
• Regular Monitoring: Regular follow-up to monitor pain levels, signs of opioid withdrawal, and any changes in opioid requirements.
• Adjustments: Dosage adjustments may be necessary based on patient response and side effects.
• Long-Term Use: The long-term benefits and safety of low-dose naloxone as an adjunct in chronic pain management require further study. Regular assessments are essential to ensure continued efficacy and safety.

References

1. McNaull, M. A., et al. (2012). “Low-dose naloxone added to patient-controlled analgesia to improve opioid analgesia and reduce opioid-related side effects: a systematic review.” Journal of Opioid Management, 8(6), 409-426.
2. Loitman, J. E., et al. (2010). “Naloxone in ultra-low doses for pain and opioid tolerance: a review.” The Journal of Pain and Symptom Management, 39(2), 336-343.