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4 Articles in Volume 2, Issue #1
Effective Approaches: Multidisciplinary Pain Management
Head Pains
Managing Pediatric Pain
Mastering Medications

Mastering Medications

This article discusses adjuvants and their application in managing pain.

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.

Introduction

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.

Antidepressants

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.

Conditions Where Antidepressants Are Helpful
Arthritis
Cancer pain
Central pain
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

The NDRI buproprion inhibits noradrenergic and dopaminergic systems, and produces a stimulant like effect (requiring some to take it only in the morning and mid-day to avoid insomnia). While not studied as an analgesic formally, it has been quite useful as a non-sedating antidepressant and is thought by some pain practitioners to be quite helpful for pain control.9 Caution is advised to keep daily doses below 450 mg total dose, never to give more than 150 mg of immediate release buproprion in any single dose, and to avoid this medication for known bulimics who use self-induced vomiting to control their weight (to lessen the risk of seizures).

Venlafaxine (a SNRI agent) is anecdotally said to possess analgesic efficacy for pain. The mechanism of action (raising the available pool of serotonin and norepinephrine) is the same for venlafaxine as the traditional tricyclic antidepressants (amitriptyline, desipramine, imipramine, nortriptyline), however, venlafaxine lacks the anticholinergic, antiadrenergic, and antihistamine effects seen with tricyclics antidepressants and may have different effects on pain modulation than the older medications.9

Trazodone and nefazodone both block serotonin-2 receptors and overall serotonin reuptake. Trazodone is more sedating than nefazodone and has a reported risk of priapism in men younger than 40 years old.9 Trazodone did not relieve the dysesthesia in a patient with traumatic myelopathy, but did have some benefit with cancer pain.15,16 Nefazadone has not been formally studied as an adjuvant analgesic, but some practitioners anecdotally claim efficacy for it.

Painful conditions improving with the use of antidepressants have traditionally included neuropathies from diabetes mellitus, postherptic, cancer (from the direct disease extension as well as from the treatments provided); headaches, both migraine and others; chronic pain conditions involving the lower back and face; and arthritis1,9,13,14,16 (See Table 1.) While not every patient responds equally to every antidepressant, there are enough similarities to suggest that these agents are likely to help many patients. More interesting, the specific antidepressant agents are dissimilar enough from one another that the failure of one medication to satisfactorily relieve pain does not absolutely predict failure of the others. Before concluding that antidepressants have no ability to relieve pain, practitioners must give each agent at least one to two months to work (with steadily increasing doses) and to consider rotation from one agent to another (even within similar classes).

One significant issue about SSRI agents, fluoxetine and paroxetine, is that both cause interferences with the CYP2D6 metabolic enzymes necessary for the conversion of codeine to morphine and hydrocodone to hydromorphone. Patients receiving these opioid medications and concomitantly taking fluoxetine, paroxetine, haloperidol, thioridazine, propoxyphene, quinidine, propafenone, ritonavir, or terbinafine may have no opioid related analgesia due to the CPY2D6 depletion.17

Anticonvulsants

Anticonvulsants, like antidepressants, are another heterogenous group of medications primarily indicated for the treatment of seizure disorders (epilepsy). More recently, studies with many of these medications have established efficacy treating neuropathic pain.1,2,18,19,20 Anticonvulsants useful in treating neuropathic pain include: carbamazepine, clonazepam, gaba-pentin, lamotrigine, phenytoin, and valproic acid. Conditions potentially benefiting from anticonvulsants are neuralgias and neuropathies, central pain states, paroxysmal pains, migraines, and phantom limb pain2,18 (See Table 2).

Historically, the anticonvulsants phenytoin, carbamazepine and valproic acid were used for neuropathic pain. There was a folklore impression that pain above the clavicles (supraclavicular) responded best to carbamazepine while pain below the clavicles (infraclavicular) responded better to phenytoin. This was never actually established, but reflected the early neuropathy literature using phenytoin for diabetic neuropathic pain (the least toxic option of the time) that was more bothersome in the lower extremities than elsewhere, and later literature after the introduction of carbamazepine describing its usefulness for the treatment of trigeminal neuralgia. Today, the “darling" of the pain world is gabapentin due to its clear efficacy for postherpetic, diabetic-related neuropathic pain and multiple sclerosis- related trigeminal neuralgia, extremely low incidence of serious toxicity and low probability of adverse drug-drug interactions.2,19-23

Conditions Where Anticonvulsants are Helpful
Neuralgias: primary (due to diseases or
trauma) or secondary (due to
medications, other therapies and
nutritional factors)
Central pain states (poststroke and
thalamic pain)
Postsympathectomy pain
Metabolic diseases (porphyria, Fabry’s
and others)
Paroxysmal pain in multiple sclerosis
Migraine headaches
Phantom limb pain

Anticonvulsants have been most useful for episodic lancinating pain syndromes with sudden onset, rapid peaking of pain, and brief durations.1 Nonlancinating pains with sudden onset also respond to the anticonvulsants. The ability of anticonvulsants to modulate these types of pain suggests that stabilization of neural membranes is critical. It is thought that these medications impact sodium channels, GABAergic inhibitory circuits and NMDA-receptors.18

Anticonvulsants studied in randomized clinical trials include carbamazepine, phenytoin, gabapentin and lamotrigine. Of these, carbamazepine and gabapentin have shown clear benefit for neuropathic pain, while lamotrigine and phenytoin have been more equivocal.18 Most studies with carbamazepine focused on trigeminal neuralgia and found response rates of 70-89 percent after five to 14 days of therapy, but due to side effects that were all too common, patients may not have been ‘blinded’ to their use of this agent.18 With a tendency to impact bone marrow and produce aplastic anemia close monitoring of all patients is mandatory when prescribing carbamazepine for any clinical situation.

Gabapentin has been most extensively studied in recent years and shown to be effective for postherpetic and diabetic peripheral neuropathies at doses ranging from 900-3600 mg per day, with excellent tolerability and no significant adverse events (compared to placebo).18-24 Due to its elimination by renal excretion practitioners are cautioned to decrease total daily dosages based upon creatinine clearance and to initiate therapy with lower doses of gabapentin.2

Lamotrigine, a newer anticonvulsant, blocking sodium channels and inhibiting glutamate release has been useful for trigeminal neuralgia, HIV neuropathy and poststroke central pain at doses of 50-400 mg per day. Because of potentially serious adverse side effects (Stevens-Johnson syndrome, dizziness, ataxia, somnolence, diplopia, and gastrointestinal problems) lamotrigine’s usefulness for neuropathic pain has been rather limited.2,18

Clonazepam, a benzodiazepine with anticonvulsant action, enhances GABAergic inhibitory activity and is thought to decrease neuronal firing. Well absorbed orally, clonazepam has been used for many years for neuropathic pain especially with hospice patients cared for at home due to its low potential for toxicity and no requirements for blood level determinations.25 Unfortunately, its high degree of sedation and lethargy has limited many patients from using clonazepam. Doses of 1-2 mg per day gradually increased to 6 mg per day have benefited many with the usual dose range being 1-4 mg per day.9 As clonazepam is a benzodiazepine medication, it must not be abruptly discontinued to prevent withdrawal syndrome (although its long half-life may afford some protection).1

Local Anesthetics

The blocking of pain with local anesthetics applied topically or administered by injection into subcutaneous tissues, nerves and their roots, and the spinal cord is well known. Systemic use of local anesthetics is less well known but has been described for lidocaine and mexiletine.1,2,18 Initial studies focused on lidocaine and demonstrated efficacy for acute and chronic pain conditions, but lidocaine’s utility was potentially limited due to medication induced toxicity26,27 (See Table 3). Of significance, one study demonstrated that the successful use of mexiletine could be predicted by the response to intravenous lidocaine.28 Subcutaneous lidocaine was found to be beneficial for some cancer patients who had not previously responded to oral local anesthetics.29 Lidocaine has been given as slowly administered intravenous boluses (100 mg) and intravenous infusions (2-5 mg/kg) over 20-30 minutes.1

Mexiletine has shown some promise for diabetic peripheral neuropathy and central pain, while other studies have failed to establish clear benefit.30-32 Despite the report that a positive response to intravenous lidocaine predicted the likelihood of success with oral mexiletine most subsequent studies have not demonstrated this to be so.18 Intolerable gastrointestinal side effects have often limited the long-term use of mexiletine for patients.

Conditions Where Local Anesthetics Are Helpful

Crescendo neuropathic pain
Neuropathic pain that is unresponsive to
other approaches
Continuous and lancinating dysesthesias

Alpha Adrenergic Agents

The only commonly used agent is clonidine that improves sympathetically maintained pain by stimulating alpha adrenoreceptors in the brainstem, thereby decreasing sympathetic outflow from the central nervous system.2 Available as both transdermal patches and oral tablets, the transdermal patches maintain the most consistent blood levels. Clonidine is often beneficial in pain syndromes that may be relatively less opioid responsive such as chronic headache, nonmalignant neuropathic pains (complex regional pain syndrome, arachnoiditis and deafferentation pain) and some cancer-related pain syndromes1 (See Table 4). While less than one quarter of patients are potential responders, those responding to clonidine experience prolonged and substantial pain relief.33,34 Dry mouth, drowsiness, fatigue, headache, lethargy, sedation, postural hypotension, skin irritation and need for site rotation all complicate therapy with clonidine even with the smallest (TTS-1) transdermal patches available.2

Conditions Where
Clonidine Is Helpful

Chronic headache
Nonmalignant neuropathic pains
(complex regional pain syndrome,
arachnoiditis and deafferentation pain)
Cancer-related pain syndromes

Antipsychotics

Little human analgesic evidence exists for antipsychotic (neuroleptic) medications despite the animal models suggesting that antipsychotic agents might be helpful.1,35 The strongest evidence for analgesic activity has been shown with methotrimeprazine, with potential analgesia suggested for pimizide and fluphenazine.1 Anecdotally, antipsychotic agents have been used alone or in combination with other medications with proposed justifications including opioid sparing effects, antidepressant potentiation, but without clear benefit despite obvious risks of toxicity (neuroleptic malignant syndrome, acute dystonic reactions, long term risk of tardive dyskinesia and all of the other known side effects and adverse reactions common to the antipsychotics) (See Table 5).

The consequence of using antipsychotics for patients suffering from pain is the functional disconnection of the limbic system (the modern-day equivalent of a noninvasive frontal lobotomy), with patients relatively unconcerned about their pain problems. This direct medication effect often permits rapid tapering of high-dose opioid analgesic medication, especially intravenous, when terminally ill patients desire to leave the hospital to return to their home hospice setting.25 By using antipsychotic medications, it is often feasible to significantly decrease the total daily opioid dosage and maintain the patient in a relaxed state. Because antipsychotic agents are powerful antiemetics, these agents do control nausea and vomiting often associated with opioid analgesics and certain medical conditions.36,37 High-potency antipsychotics medications, like droperidol and haloperidol, are useful as antiemetics since they produce minimal effects on the cardiovascular system.

Conditions Where Antipsychotics Are Helpful
Opioid sparing effects
Antidepressant potentiation
Nausea and vomiting

Antispasmodics

Baclofen and cyclobenzaprine are the most common of these agents. Baclofen may possess analgesic properties and augment opioid-induced analgesia via GABA-B agonist actions, while cyclobenzaprine relieves muscle spasm of local origin without interfering with normal muscle function.2 Baclofen has been demonstrated to have efficacy in trigeminal neuralgia and is considered a second line option for trigeminal neuralgia after carbamezapine.38,39 Cyclobenzaprine has not been as well studied as baclofen but may be helpful for acute painful musculoskeletal conditions. Baclofen is started slowly (5 mg two to three times daily) and titrated to 30-90 mg per day or higher if tolerated. Baclofen and cyclobenzaprine have common side effects including sedation, dizziness, and gastrointestinal difficulties but baclofen has the additional risk for serious withdrawal syndrome if discontinued too rapidly (it must be tapered before discontinuation).1

Conditions Where Antispasmodics Are Helpful
Acute muscle spasms
Spasticity due to neurological disease or
injury
Trigeminal neuralgia

Psychostimulants

Psychostimulants, dextroamphetamine and methylphenidate, are useful for the relief of depression, diminishing excessive sedation due to opioids, potentiating the analgesic effect of opioids in patients with postoperative and cancer pain, improving appetite, promoting a sense of well-being, and lessening feelings of weakness and fatigue.40 Dextroamphetamine has reported analgesic efficacy for postoperative pain, while dextroamphetamine methylphenidate and pemoline have been recommended for pain management near the end of life.1,10,41,42 Doses of dextroamphetamine and methylphenidate commonly utilized are 5-10 mg once or twice daily (breakfast and lunch), with few patients requiring more than 30 mg per day.10 Although pemoline lacks abuse potential (so has a low DEA scheduling permitting telephone orders), has mild sympathomimetic effects, and comes in a chewable tablet form that can be absorbed through the buccal mucosal, it is not established that it potentiates opioids even as it counters the sedation of opioids and relieves depression; additionally, it should be used with caution with patients having underlying liver disease.40

Conditions Where Psychostimulants Are Helpful
Depression
Postoperative pain
Pain near the end of life

NMDA Antagonists

Ketamine, a NMDA-receptor antagonist, may benefit a variety of chronic neuropathic pain states (including phantom limb pain and postherpetic neuralgia) and perhaps improve acute pain syndromes through its modulation of glutamate mediated “wind up."43 At subanesthetic doses ketamine does not suppress cardiovascular function, laryngeal protective reflexes and causes less respiratory compromise than opioid analgesics.1 Unfortunately, ketamine is associated with a severe side effects profile involving dizziness, dysphoria, frightening dreams and hallucinations.1 Commercial preparations of ketamine are all currently for parenteral administration. If other dosing routes become available, perhaps ketamine may play a greater role in pain management.

Dextromethorphan has been a potential alternative to ketamine for the treatment of diabetic neuropathic pain although it has not been effective for postherpetic neuralgia.44 Due to significant side effects and potential for serious drug-drug interactions when combining dextromethorphan with serotonin enhancing medications (antidepressants), researchers continue to develop other less toxic NMDA antagonists. Perhaps in the future one of these agents may prove useful for a variety of painful disorders.

Conclusion

While the adjuvant analgesics often prove beneficial for many patients suffering from a wide range of painful disorders, there remain no “single best" agents for all situations. Modern pain practitioners must continue to learn more about the current medications, evaluate emerging clinical trials and advocate for patients and their pain. Clearly, these medications taken as a whole have been helpful for specific painful disorders. As researchers continue to learn more about the underlying processes for the transmission and modulation of pain adjuvants will increasingly become more important and much more tailored. This is an exciting and evolving area of pharmaceutical science. n

Last updated on: May 16, 2011
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