James A.D. Otis, MD, Michael Perloff, MD, PhD, and Gina Deck, MD
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Medications can provide effective pain management in most patients. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the principal medications for somatic pain, whereas adjuvant medications such as antidepressants, antiepileptics, anesthetics, and adrenergic agents are useful for neuropathic pain. Severe pain, whether somatic or neuropathic, usually requires opioid therapy.
NONOPIOID ANALGESICS
Nonsteroidal Anti-inflammatory Drugs
NSAIDs are indicated for somatic pain of mild-to-moderate intensity, particularly for bone or joint pain. The proposed mechanism of NSAID analgesia is inhibition of cyclooxygenase activity (COX), which in turn inhibits prostaglandin production. Side effects include nausea, diarrhea, and less commonly, gastric or duodenal ulceration. Other well-known side effects include renal damage and hematologic toxicity, primarily platelet inhibition. In an attempt to decrease the toxicity of traditional NSAIDs, COX-2 selective inhibitors were developed. However, subsequent studies demonstrated increased myocardial infarctions and strokes in recipients of COX-2 inhibitors. Rofecoxib and valdecoxib have been withdrawn from the market. Celecoxib is still available, but with a black box warning for cardiovascular risk.
Adjuvant Analgesics
Medications that have a primary indication other than analgesia, but which have analgesic properties under certain conditions, are termed adjuvant analgesics.
Antidepressants
The tricyclic antidepressants (TCAs) have been used for many years for the management of neuropathic pain, most effective for continuous, burning, or dysesthetic pain. The greatest analgesic effect is seen with the older, tertiary amine antidepressants, such as amitriptyline, imipramine, and doxepin. The most common side effect is sedation, which can be avoided by starting at a low dose and instructing the patient to take the medication 10 to 12 hours before rising. TCAs are contraindicated in patients with glaucoma, cardiac arrhythmias, and prolonged QTc. Some patients are not able to tolerate TCAs and may benefit from some of the newer antidepressants, specifically serotonin–norepinephrine uptake inhibitors. Venlafaxine has demonstrated efficacy in peripheral neuropathy, postmastectomy pain syndrome, fibromyalgia, migraine and tension headache, and painful diabetic neuropathy. Similarly, duloxetine can be used in peripheral neuropathy and fibromyalgia. These two medications may be the preferred drugs for the treatment of depression with comorbid pain syndromes. Advantages over classic TCAs include fewer anticholinergic effects, less alpha blockade (less orthostasis), and absence of QTc prolongation.
Anticonvulsants
Anticonvulsant/antiepileptic drugs (AEDs) may reduce pain by reducing neuronal excitability and local neuronal discharges. AEDs appear to be helpful in pain syndromes that are characterized by paroxysmal or lancinating pain, as well as burning pain and allodynia. Phenytoin, the first AED used for pain, was found to be effective for the management of trigeminal neuralgia and postherpetic neuralgia. Carbamazepine appears to be more effective than phenytoin. Important side effects of carbamazepine include hyponatremia, dizziness, somnolence, and significant leukopenia. Starting at a low dose and gradually escalating in 100-mg increments every 3 to 7 days can minimize the dizziness. Oxcarbazepine may be useful in spinal cord injury pain, radiculopathy, and diabetic neuropathy, as well as carbamazepine nonresponsive trigeminal neuralgia. The toxicity of oxcarbazepine is less than that of carbamazepine. Valproic acid has been used for the management of lancinating pain, for pain of diabetic neuropathy, but the more established efficacy is in the management of migraine headaches. The large number of drug interactions and significant hepatic dysfunction that can occur with this drug make it a second-line choice.
Gabapentin has demonstrated efficacy in both lancinating and continuous dysesthetic pain. Gabapentin is a remarkably well-tolerated drug with few interactions and a good side effect profile. The most common reported side effect is somnolence, which diminishes after the first 2 weeks of therapy. A newer AED, pregabalin, has a very similar profile to gabapentin and is effective in neuropathic pain. Side effects of both of these medications include dizziness, somnolence, and weight gain. However, pregabalin may be better tolerated and can be dosed twice daily.
Oral Anesthetics
Neuropathic pain has been found to respond transiently to high doses of intravenous local anesthetics, such as lidocaine. The most common side effects are dose related and include nausea, dizziness, and tremors. Typically, local anesthetics are used more for acute pain syndromes and in inpatient settings relating to cancer therapy and surgery. Ketamine, an NMDA receptor agonist, also has a role in chronic pain. The most common side effects of systemic ketamine include vivid dreaming, dysphoria, cognitive impairment, nausea, vomiting, and dizziness.
Medical Marijuana
Despite all of the treatments previously mentioned, many patients have refractory chronic neuropathic pain. In some of those patients, smoked cannabis was shown to be useful for pain relief. No study has yet shown prolonged analgesia from smoked cannabis or from pharmaceutically available cannabinol or dronabinol. Although it is difficult to summarize the risks and benefits of cannabinoids, it is probably fair to say that there is no doubt that cannabinoids can have therapeutic effects, including analgesia, at least in the short term. A fuller understanding of cannabinoids’ analgesic efficacy awaits further research.
Alpha Agonists
The α2-adrenergic agonists have been studied in a variety of pain syndromes. The mechanism of action is presumed to be an enhancement of endogenous pain-modulating systems and, in the case of sympathetically maintained pain, sympatholysis. Clonidine can be administered epidurally, intrathecally, orally, or transdermally. The major limiting factors in its use are hypotension and sedation. Tizanidine, a newer spasmolytic agent, has been shown to have antinociceptive properties, particularly in muscle and soft tissue pain. It is as effective as baclofen in decreasing spasticity but may be more sedating.
Topical Agents
Topical agents are most useful in painful neuropathies, herpetic and postherpetic neuralgia, and occasionally painful arthropathies. Capsaicin, a naturally occurring pepper extract, has been found to be useful in reducing neuropathic pain in diabetics. Its main side effect is a burning sensation, and patients often are not able to tolerate it. A new formulation of capsaicin, an 8% dermal patch, has demonstrated promising effects in painful neuropathies, specifically HIV neuropathy. Lidocaine patch use has become popular as a treatment for neuropathic pain and is indicated for pain of postherpetic neuralgia. Diclofenac, as a transdermal patch or gel, is the most commonly prescribed topical NSAID. Side effects are the same as oral diclofenac (GI ulcer, blood dyscrasias, renal, and hepatotoxic), but to a markedly lesser extent than systemic usage.
Muscle Relaxants
Spasmolytic agents such as baclofen, tizanidine, and benzodiazepines are useful for conditions that produce flexor and extensor spasms because of neural injury, as well as chronic muscle spasm. Patients with spasticity related to multiple sclerosis or upper motor neuron lesions from trauma, cerebrovascular disease, or degenerative disease might benefit from baclofen. The major side effect of baclofen is mild sedation. Cyclobenzaprine is a tricyclic agent that has been marketed as a muscle relaxant. Its major site of action appears to be in the brainstem, although the exact mechanism of action is unclear. It is indicated for short-term use only and can be quite sedating.
KEY POINTS
1. There are a variety of nonaddictive nonopioid pharmacotherapy options for pain.
2. Many options used for analgesia have FDA-approved indications for other conditions such as TCAs for depression.
3. Antiepileptics, anesthetics, and adrenergic agents are useful for neuropathic pain.
REVIEW QUESTIONS
1. A 40-year-old woman with depression and hypertension sees you with painful diabetic neuropathy. She has tried gabapentin, amitriptyline, and capsaicin cream. What is a reasonable medication to initiate?
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