The role of adjuvant medications for the control of pain has been known for many years. Exactly which agents to use and why remains rather mysterious for most clinicians. The relative advantages of one medication or one class of medications over another are not clear for all circumstances. Today, practitioners are required in many states to obtain further education in pain management and to master the role of adjuvant medications. This article discusses the role of adjuvants in modern pain management.
Adjuvant analgesics are medications with a primary indication other than pain that may be analgesic in some painful conditions.1 Adjuvants are used for the treatment of non-pain conditions such as cardiac arrhythmias, depression, and epilepsy, yet possess analgesic effects secondary to their primary indications.2 Curiously, adjuvants may be added to existing treatment strategies involving non-steroidal anti-inflammatory medications and/or opioid analgesics to improve outcome or they may be used alone as the primary therapy for certain conditions.
Adjuvants typically include anticonvulsants (antiepileptics), antidepressants, antipsychotics, anxiolytics, local anesthetics, corticosteroids, and stimulants. Focusing on their presumed mechanisms of action, these medications functionally include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), sodium channel blockers, GABAergics, benzodiazepines, alpha adrenergics, and others.2
Confusion exists regarding these medications between palliative care, pain, and psychiatric literature. Adjuvants are called coanalgesics in palliative care literature, but these are the same medications that pain practitioners utilize when prescribing adjuvant analgesics.1 Psychiatrists refer to these medications as psychotropic agents in general, but refer to anticonvulsants as mood stabilizers and antipsychotics as neuroleptics and major tranquilizers. Regardless of what adjuvants agents are called, they are very useful for a variety of painful disorders and are generally safe for most patients under a wide range of circumstances.
These are some of the most widely prescribed adjuvant medications for the management of pain. Early placebo-controlled trials determined their potential for use in patients suffering from the pain of tension headache and post-herpetic neuralgia involved primarily amitriptyline.3,4 Headache researchers thought that a vasodilator effect, not a mood enhancement alteration, accounted for the pain relief, while post-herpetic neuralgia researchers postulated that the antidepressant action was essential for pain relief to occur.5 Later work suggested that by adding an antipsychotic medication (fluphenazine) to the antidepressant (usually amitriptyline) might improve the pain relief associated with neuropathy when amitriptyline alone had not been effective.6 Placebo-controlled studies of amitriptyline showed that the medication benefited patients with postherpetic neuralgia who were free of depression or other psychiatric conditions leading to the theory that the potentiation of serotonin (5-HT) and norepinephrine (NE) pathways descending from the brain to the spinal cord might be the mechanism for pain relief.7,8
Traditional tricyclic antidepressants (amitriptyline, clomipramine, desipramine, doxepin, imipramine, and nortriptyline) all inhibit the reuptake of NE, 5-HT, or both at the spinal dorsal horn synapses to thereby modulate pain.5 More recently developed SSRIs only inhibit the reuptake of 5-HT (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) while serotonin-norepinephrine reuptake inhibitors (SNRIs) inhibit the reuptake of 5-HT at lower doses but then inhibit the reuptake of NE at higher doses (venlafaxine).9 Norepinephrine and dopamine reuptake inhibitors (NDRIs) selectively inhibit the reuptake of catecholamines (buproprion) while serotonin-2 antagonist/reuptake inhibitors (SARIs) are able to block certain types of serotonin binding sites while simultaneously increasing the overall pool of serotonin (trazodone and nefazodone). Older monoamine oxidase inhibitors (MAOIs), such as isocarboxacid, phenel-zine, and tranylcypromine, inhibit the breakdown of catecholamines in synaptic junctions, but are more problematic to work with for most patients and therefore are rarely used by pain practitioners or psychiatrists today. While the subtleties of the various receptor types and neurotransmitter molecules may seem complicated, all of these medications in some way manipulate the levels of dopamine, norepinephrine, and serotonin, or impact the receptor binding sites for these neurotransmitters to produce their clinical effects.
Chronic facial pain
Chronic lower back pain
Headaches (migraine and others)
Neuropathic pain (diabetic, mixed, postherpetic)
Today, TCAs are less in vogue than they were in the past. Instead of primarily relying upon amitriptyline and imipramine for burning pain, more recent literature recommends the use of their metabolites, nortriptyline and desipramine, respectively.10 So toxic are amitriptyline and imipramine for elderly, sick patients that the Education for Physicians on End-of-life Care curriculum describes desipramine as the tricyclic antidepressant of choice in seriously ill people, with nortriptyline as an alternative and virtually no further use of either parent molecule.10
Regardless of which TCA is given, time to clinical response is often measured in weeks. Side effects (dry eyes, dry mouth, urinary hesitancy, constipation, orthostatic hypotension, confusion, delirium) are so common and often limit the dose that may be given to older, more fragile patients that many practitioners try to avoid their use as first-line agents. Due to these side effect issues and other toxic manifestations, practitioners wishing to use TCAs must be patient and watch clinical effects gradually increase over weeks and while they continue to increase doses prescribed until either pain relief occurs or overt toxicity is noted.9
To avoid TCA complications, many practitioners now look to the other antidepressant options including the SSRIs, SNRIs, NDRIs and SARIs (so-called atypical antidepressants). While less studied in double blind placebo controlled trials than the older tricyclic antidepressants, some of these newer agents are promising as adjuvant therapies for certain painful conditions. SSRIs, however, have generally been less beneficial than expected for painful conditions except potentially paroxetine for neuropathy-related pain11,12 and fluoxetine for rheumatic pain conditions.13 Fluoxetine trials for the treatment of neuropathic pain failed to demonstrate analgesic activity despite a long held theory that endorphin release followed midbrain serotonin levels.14