• Methocarbamol 750 to 1500mg three times daily • Metaxalone 800mg 3 to 4 times daily • Tizanidine 4 to 8mg three times daily as needed Use of muscle relaxants is associated with significant adverse events, including drowsiness and dizziness. Sedation can be significant, and can limit the patient’s ability to drive or work; these effects are more likely in older patients and those with organ dysfunction. Combination with other sedating agents such as opioids and benzodiazepines can exacerbate sedation. It may be best to avoid the use of muscle relaxants in patients with substance use disorders, particularly those who are also utilizing opioids, due to the significant risk of misuse. Use of muscle relaxants should be limited to adjunctive therapy for short-term treatment of acute musculoskeletal conditions. 111,134 Benzodiazepines Benzodiazepines are Schedule IV controlled substances that work by potentiating the inhibitory activity of GABA and increasing its ability to exert calming effects. This effect can be helpful in the treatment of anxiety, but can also be addictive 135 . Benzodiazepines are also effective in treating muscle spasms, though their high abuse potential and availability of alternative agents for this purpose make them a non-preferred agent for the treatment of chronic pain. 111,129 The most commonly reported side effects associated with benzodiazepines are related to central nervous system depression: drowsiness, amnesia, psychomotor impairment, and confusion. Drowsiness is more commonly experienced during the first few days of treatment though tolerance can develop to this side effect. Rebound anxiety can occur after short-term treatment; higher doses can result in withdrawal symptoms and learning impairment. Benzodiazepines with shorter half- lives, such as alprazolam and lorazepam are more likely to cause acute withdrawal when abruptly stopping treatment after prolonged use. Those with longer half-lives, such as diazepam, typically produce more delayed and attenuated withdrawal symptoms. 111,135 Benzodiazepines must be tapered very slowly when discontinuing after long-term use. A reduction of around 10% per 1-2 weeks is preferred if circumstances allow. Patients should be monitored for symptoms of withdrawal such as anxiety, dysphoria, tremor, perceptual disturbances, psychosis, or even seizures. If withdrawal symptoms develop, the rate of dose reduction should be slowed accordingly. 111,135 Drug interactions must also be considered when prescribing benzodiazepines. Because they exert depressant effects on the central nervous system (CNS), administration of additional CNS depressants such as opiates, muscle relaxers, sleep medications, and alcohol should be minimized because of the risk of respiratory depression and death. 111
The U.S. Food and Drug Administration added a black box warning to the labels of all opioids and benzodiazepines advising against using these medications together. Because both are CNS depressants, the combination puts patients at increased risk of slowed or difficult breathing, oversedation, respiratory depression, and death. The CDC recommends that these medications should be prescribed together only when alternative treatments are inadequate. When co-prescribed, the dosages and durations should be kept to the minimum possible. 118 Benzodiazepines must be used especially cautiously in the elderly. Elderly patients are more susceptible to drug accumulation because of hepatic insufficiency, decreased oxidation, and altered volume of distribution. They are also more sensitive to the central nervous system effects of benzodiazepines regardless of the half-life of the agent used. This results in an increased frequency of falls and associated fractures. 111 Benzodiazepines should be avoided in pregnant patients. Teratogenic effects such as cleft lip and cleft palate have been associated with benzodiazepine use, particularly during the first trimester, when fetal development is rapid. Benzodiazepine use during the third trimester has been associated with neonatal withdrawal, sedation, and hypothermia in the infant. 111 Antidepressants Antidepressants are an important modality in the treatment of many painful conditions. Antidepressants seem to work best for treating neuropathic types of pain, such as neuropathy, nerve damage (post-herpetic neuralgia), migraine, and fibromyalgia. They may also be helpful adjuvants in lower back pain, arthritis, and pelvic pain. The mechanism by which these drugs address pain is not clearly understood, but it is thought that inhibiting norepinephrine reuptake leads to the up-regulation of inhibitory pain pathways. Antidepressants take two to four weeks to exhibit analgesic effects, so some patience is required. 111,129 The evidence is most supportive of the use of tricyclic antidepressants (TCAs) and serotonin- norepinephrine reuptake inhibitors (SNRIs) for the treatment of pain. Studies have shown that only 3.6 to 6.4 patients with neuropathic pain need to be treated for one patient to achieve at least a 50% reduction in pain relief. TCAs and SNRIs are indicated for the treatment of pain even in the absence of mood disorders, since analgesic effects are known to occur in patients who are not depressed. However, their use in patients with comorbidities of depression and pain can provide significant benefits in the treatment of both disease states. 111,129 Among the SNRIs, duloxetine and venlafaxine have the most evidence for use in neuropathic pain, and duloxetine also has evidence of efficacy in musculoskeletal pain. Duloxetine is FDA approved for the treatment of fibromyalgia, chronic low back pain, osteoarthritis and diabetic neuropathy.
It is typically used in doses of 30 to 120mg daily, with lower doses preferred in patients who are concerned about side effects. Duloxetine should be avoided in patients with hepatic or severe renal insufficiency. Venlafaxine is used in doses of 75- 225mg daily for the treatment of acute and chronic neuropathic pain. 111,129 SNRIs are contraindicated in patients taking MAOIs within the previous two weeks due to the risk of serotonin syndrome, and in some cases, hypertensive crisis. Duloxetine has moderately potent inhibitory effects on the hepatic cytochrome P450 enzyme CYP2D6, resulting in drug interactions with other medications that affect or are affected by this enzyme. Side effects associated with SNRIs include 136 : • Nausea, which appears to diminish over time • Dizziness • Diaphoresis • Increased blood pressure, due to the effects on norepinephrine • Headaches • Sexual dysfunction • Increased risk of bleeding • Hyponatremia While tricyclic antidepressants do not carry FDA approval for pain management, they are used frequently for a number of chronic pain states. Amitriptyline is the most widely studied TCA in chronic pain and is the only TCA with proven efficacy in migraine prevention. When used for pain, amitriptyline can be started at 25mg at bedtime, and slowly increased at weekly intervals up to 125mg daily. Nortriptyline is also used for chronic pain and may be preferred due to its reduced anticholinergic and sedative effects when compared to amitriptyline. Nortriptyline can be started at 10mg daily at bedtime and increased weekly in 10 to 25mg intervals up to 75 to 150mg daily. TCAs should be started at low doses, and doses should only be increased slowly as needed. Low starting doses are particularly important when using TCAs in older adults, who are at a higher risk of being negatively affected by side effects. 129 Since TCAs are sedating, administration with barbiturates, alcohol or other agents with CNS depressant effects can cause oversedation, impaired functioning, and falls. Medications that increase serotonin levels, including herbal preparations such as St. John’s wort and SAM-e, can lead to serotonin syndrome when co-administered. Agents that cause QT prolongation, such as certain broad-spectrum antibiotics, should be used with caution with cyclic antidepressants, due to additive risk. Other agents that lower the seizure threshold, such as tramadol, can increase the risk of seizures when administered with cyclic antidepressants. Side effects associated with cyclic antidepressants include 137 : • Overdose: as little as 10 times the daily dose of cyclic antidepressants can be fatal, due to QT prolongation causing fatal arrhythmias • Cardiac side effects, such as orthostatic hypotension, QT prolongation, tachycardia and arrhythmias • Lower seizure threshold
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