Adjuvant Analgesics

Based on "Essential Pain Pharmacology"
written by Howard S. Smith MD, Marco Pappagallo MD

What are Adjuvant Analgesics?

Adjuvant analgesics (co-analgesics) are not analgesics in the true pharmacological sense. They are developed primarily for treating medical conditions other than pain. However, adjuvant analgesics may contribute significantly to pain relief when used either alone or in combination with other analgesics.

Adjuvant analgesics comprise a diverse group of medications with different therapeutic indications and include:

  • Antidepressants
  • Anticonvulsants
  • Cannabinoids
  • Bisphosphonates
  • Antiarrhythmics2.

Benefits that can provide adjuvant analgesics6:

  • Improved analgesic efficacy of traditional pain medications.
  • Reduced opioid-related adverse effects.
  • Additional therapeutic effects for insomnia, anxiety, and depression.
Co-analgesics may be used alone or in combination with a conventional pain medications to treat persistent pain conditions of different origin, particularly neuropathic pain (a form of chronic pain caused by injury to or disease of the peripheral or central nervous system).


Antidepressants have been used for decades as primary analgesics. They may provide analgesia for different types of pain, but not all and not to the same degree.

The tricyclic antidepressants (TCAs) have been well studied and are most likely to be effective. TCAs (such as amitriptyline, nortriptyline, and desipramine) have demonstrated efficacy for pain caused by:

  • nerve damage from diabetes and shingles
  • headache and migraine
  • fibromyalgia
  • neck and back radicular pain


The most evidence exists for amitriptyline but some patients cannot tolerate its numerous sedating and anticholinergic effects. Desipramine or nortriptyline are be better tolerated.

Controlled studies of the tricyclic antidepressants have shown that effective analgesic dose is often lower than that required to treat depression, and the onset of analgesic action usually is earlier.

TCAs are probably more effective at relieving neuropathic pain than the newer antidepressants, but frequently induce poorly tolerated side effects. The newer antidepressants, selective serotonin and norepinephrine reuptake inhibitors (SNRIs) and serotonin-selective reuptake inhibitors (SSRIs) have fewer side effects than TCAs.

Unfortunately, SSRIs lack efficacy in pain relief. Paroxetine is the only SSRI that has some evidence for modest efficacy in treating chronic pain.

SNRIs appear to be more effective analgesics than the SSRIs.

Venlafaxine is sometimes prescribed for:

Duloxetine, the newest of the SNRIs has been approved by the FDA as a treatment for:

  • Pain due to diabetic neuropathy
  • Fibromyalgia
  • Chronic musculoskeletal pain

Bupropion, which is predominantly noradrenergic, has also shown evidence to alleviate pain.

The precise painkilling mechanism of antidepressants remains unknown. They may increase neurotransmitters in the spinal cord that reduce pain signals. Antidepressants may also exert additional therapeutic effects through histamine receptors as well as modulation of sodium channels3. They don't work immediately. You may have to take an adjuvant for several weeks before it starts reducing the pain.


Anticonvulsants have been used in the management of pain since the 1960s. There is strong evidence that anticonvulsants are useful in reducing neuropathic pain, especially when the pain is lancinating or burning. They act by suppressing the spontaneous neuronal discharges and neuronal hyperexcitability that occur after nerve injury and may also have a central effect.

Carbamazepine, an anticonvulsant structurally related to tricyclic antidepressants, was the first representative from this class to be studied in clinical trials.

Carbamazepine is used for the management of:

  • Trigeminal neuralgia
  • Painful diabetic neuropathy
  • Postherpetic neuralgia.

Gabapentin is currently widely used for neuropathic pain.
Gabapentin is effective for:

  • Diabetic painful polyneuropathy (FDA approved indication)
  • Postherpetic neuralgia (FDA approved indication)
  • Persistent post-operative and post-traumatic pain
  • Headaches
  • Migraines

Gabapentin mechanisms of action are still not fully defined, but it is effective in relieving indexes of allodynia and hyperalgesia in animal models.

Pregabalin, which has mechanism of action similar to gabapentin. It has stable pharmacokinetics and simple dosing.

Pregabalin uses in painful conditions:

  • Diabetic peripheral neuropathy (FDA approved indication)
  • Post-herpetic neuralgia (FDA approved indication)
  • Fibromyalgia (FDA approved indication)
  • Adjunctive analgesia for acute pain

See also Gabapentin vs Pregabalin for postoperative pain

Lamotrigine has shown some efficacy for carbamazepine-resistant trigeminal neuralgia.

Other antiepileptics, such as phenytoin, clonazepam, valproic acid, topiramate, tiagabine, and oxcarbazepine, also have antihyperalgesic and antinociceptive effects, and are used for neuropathic pain.

Recently anticonvulsants have been examined for adjuvant use for postoperative pain. Similar to nerve injury, surgical tissue injury is known to produce neuroplastic changes leading to spinal sensitization and the expression of stimulus-evoked hyperalgesia and allodynia.

Alpha-2-adrenergic agonists

Alpha-2-adrenergic agonists are known to have a spinal antinociceptive effect via alpha-2 receptor subtypes. Animal studies and clinical experience indicate some usefulness of clonidine, tizanidine and dexmedetomidine for several painful states.

Alpha-2 agonists can induce analgesia by acting at three different sites: in brain, spinal cord and in peripheral tissues. These drugs have little or no respiratory depression.

Clonidine is a potent analgesic with sedative and anxiolytic properties. Clonidine potentiates the analgesic effect of opioids. Additionally, clonidine effect may be enhanced by amitriptyline. The drug is suitable for the management of patients with opioid tolerance. Clonidine can be used alone or in combination with other pain relievers.

Dexmedetomidine has sedative, anxiolytic, analgesic, and blood pressure lowering properties. Dexmedetomidine is used as an anesthetic adjunct to decrease dosages of other anesthetic agents. It is also used peri-operatively in critically ill patients.

NMDA antagonists

Ketamine is a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptors. It is a central-acting anesthetic and analgesic. Ketamine produces antinociceptive action via inhibition of NMDA receptors and activation of descending inhibitory monoaminergic pain pathways. However, ketamine is rarely used as a sole analgesic because it has a narrow therapeutic window and can cause intolerable side effects.

Low-dose ketamine is often used as an adjuvant to opioid analgesia. Ketamine (used as an adjuvant to opioids) appears to increase pain relief by 20% to 30% and allows opioid dose reduction by 25% to 50%.

Memantine, a NMDA receptor antagonist, is used for neuropathic pain. Its primary indiaction is treatment of Alzheimer dementia.

Dexromethorphan is chemically related to codeine and morphine. It acts as a low-affinity NMDA receptor antagonist and may relieve somatic and neuropathic pain.

Further reading


References & Resources

  • 1. The Merck Manual of Medical Information. Mark H. Beers et al., eds. 2nd Home Edition. Whitehouse Station, NJ: Merck; 2003.
  • 2. Knotkova H, Pappagallo M. Adjuvant analgesics. Med Clin North Am. 2007 Jan;91(1):113-24.
  • 3. Sawynok J, Esser MJ, Reid AR. Antidepressants as analgesics: an overview of central and peripheral mechanisms of action. J Psychiatry Neurosci. 2001 Jan;26(1):21-9. PubMed
  • 4. Worner J, Rukwied R, Konrad C. Co-analgesics - today and tomorrow. Anasthesiol Intensivmed Notfallmed Schmerzther. 2009 Nov;44(11-12):736-44.
  • 5. Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg. 2004 Aug;99(2):482-95
  • 6. Lui F, Ng KF. Adjuvant analgesics in acute pain. Expert Opin Pharmacother. 2011 Feb;12(3):363-85. PubMed
  • 7. Gálvez R, Caballero J, Atero M, Ruiz S, Romero J. Venlafaxine extended release for the treatment of chronic pain. A series of 50 cases. Actas Esp Psiquiatr. 2004 Mar-Apr;32(2):92-7.

Published: May 05, 2007
Last updated: September 01, 2017


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