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Opioid Prescribing and Monitoring
How to Combat Opioid Abuse and Misuse Responsibly

Think Combination Therapies

Anticonvulsant medications (ACMs) are usually considered the first-line treatment for the management of neuropathic pain. A course of antidepressants would typically follow. While titrating to optimal dosages, which may take as long as 2 months, immediate-release opioids may be helpful. However, the use of extended-release opioids is not usually initially recommended.

Polypharmacy (combination therapy) is commonly used, which means the physician must understand the pharmacology of the various drugs. Both older (conventional) and newer ACMs may be used in patients with neuropathic pain, migraine, fibromyalgia, essential tremor, spasticity, restless leg syndrome, and low back pain, as well as several psychiatric disorders, including bipolar disorder and schizophrenia (Table 1).1-5

When using ACMs, here are some clinical pearls to improve their effectiveness:

  1. Always start low and go slow when titrating an ACM.
  2. Understand the pharmacokinetics as well as mechanistic differences between the ACMs.
  3. In treatment-resistant patients (those with poor effectiveness), it is useful to combine 2 ACMs, if necessary, but be certain to use drugs with different mechanisms of action.
  4. All too often a patient will state that he or she has tried and failed on an ACM, or more than 1 ACM. Be certain to find out exactly what happened. Most commonly, the patient took a very low dose of an ACM for a very short period of time (less than what would be necessary to develop a steady state with clinical efficacy) and claimed lack of effectiveness. At that point, instead of the physician insisting that the titration be continued appropriately, a different ACM is used, and the same problems persist. If an ACM is not titrated appropriately, the drug was really not used, and there would have been no clinical effectiveness. Stopping a drug due to adverse effects is absolutely appropriate.
  5. Push the ACM dosages until you see clinical effectiveness or have to stop it due to adverse effects.
  6. In many patients, maximal effectiveness (in the treatment of neuropathic pain) is found with ACMs given at 50% to 100% of their anti-epileptic dosages. This does not hold true for ACMs approved by the US Food and Drug Administration (FDA), which were approved at specific dosages for the treatment of neuropathic pain.

ACMs are FDA approved for the treatment of trigeminal neuralgia, postherpetic neuralgia (PHN), diabetic neuropathy, as well as central pain.6,7 These agents may also relieve burning dysesthesias. Chemically, ACMs are a diverse group of drugs, typically highly protein bound, and undergo extensive hepatic metabolism.

Anticonvulsant Agents

Almost immediately after it was approved by the FDA in 1993 for use as an adjunctive treatment in adults with partial epilepsy, physicians also began to use gabapentin for various neuropathic pain disorders, such as diabetic peripheral neuropathy (DPN) and PHN.8-10 Gabapentin's benign side effect profile, especially in comparison to tricyclic antidepressants (TCAs), quickly made it very popular among physicians. It is now the most commonly prescribed ACM.

Over time, a growing consensus concerning the usefulness of gabapentin in reducing pain has emerged, supported by well-controlled clinical trials.11 Gabapentin appears to act primarily at the alpha 2 delta (α2δ) subunit sites on the calcium channels, and has been shown to be effective in reducing pain behavior in a model of central sensitization and neuropathic pain, as well as in lessening spinally mediated hyperalgesia seen after sustained nociceptive afferent input caused by peripheral tissue injury.12,13 Gabapentin also appeared to enhance spinal morphine analgesia in a laboratory model of nociceptive pain.13

Further research suggests gabapentin is effective in reducing painful dysesthesias and improving quality-of-life scores in patients with painful DPN.14 Research comparing gabapentin with amitriptyline for diabetic neuropathy found both to be equally effective.15 However, the number needed to treat (NNT) for the TCAs is 2.5, compared to 4.2 for gabapentin.16-18

Gabapentin is now FDA approved and considered a first-line therapy for PHN, another difficult neuropathic pain syndrome that affects approximately 10% to 15% of patients who develop herpes zoster. Only about half of patients obtain adequate relief with antidepressants. Research has found a modest but statistically significant pain reduction for patients treated with gabapentin compared with controls.19 Gabapentin also appears to improve sleep and quality-of-life scores. Adverse reactions include somnolence, dizziness, and infection.

Overall, gabapentin is generally well tolerated, even in the geriatric population, and has a safer side effect profile than TCAs. In the PHN study, the majority of patients were titrated to 3600 mg daily, and the median patient age was 73. Because the kidneys excrete gabapentin, the dosage must be reduced for patients with renal insufficiency.20 Also critical to note, the bioavailability of gabapentin is inversely proportional to dose, secondary to saturable absorption.21

Behind gabapentin, pregabalin (Lyrica) is the next most commonly used ACM. The agent reduces the release of excitatory neurotransmitters (e.g., glutamate, norepinephrine, serotonin, dopamine, and substance P) and has been FDA approved for the treatment of neuropathic pain associated with DPN, PHN, and fibromyalgia, and as adjunctive treatment of partial seizures.21-26 Several randomized clinical trials show pregabalin to be superior to placebo in the treatment of PHN and DPN at doses of 300 to 600 mg daily.27-30 Improvements in sleep have also been seen. The most common adverse effects include dizziness, somnolence, peripheral edema, infection, and dry mouth.22-23

Pregabalin was the first drug approved for use in fibromyalgia, based on two initial randomized clinical trials of approximately 1800 patients.31 Researchers found patients treated with pregabalin compared to placebo had lasting improvement on the patient global impression of change.32 At 600 mg daily, it appeared no more effective than the lower doses, and there was evidence of dose-related side effects.31 Again, the agent should be used at lower doses in patients with renal insufficiency.22,23

Carbamazepine also has a long history of use for lancinating neuropathic pain, including trigeminal neuralgia, and is the most appropriate ACM to use for lancinating pain. It is chemically related to the TCA imipramine, has a slow and erratic absorption, and may produce numerous side effects, including sedation, nausea, vomiting, and hepatic enzyme induction.

In 10% of patients, transient leukopenia and thrombocytopenia may occur, and hematologic changes may persist and require stopping the drug in 2% of patients.33-35 Aplastic anemia is the most severe complication associated with carbamazepine and may occur for 1 in 200,000 patients. Although requirements for hematologic monitoring remain debatable, a complete blood cell count, hepatic enzymes, blood urea nitrogen, and creatinine are recommended at baseline. These should be checked again at 2, 4, and 6 weeks, and every 6 months thereafter. Carbamazepine levels should also be drawn every 6 months, as well as after changing the dose, to monitor for toxic levels and to verify that the drug is within the therapeutic range (4 to 12 mg/mL). Check the patient’s electrocardiogram, if it has not been done recently, to look for arrhythmias and evaluate the QT interval.

Patients with low pre-treatment white blood cell (WBC) counts are at increased risk of developing leukopenia (WBC<3000/mm3). Because toxicity is entirely unpredictable, it is important to instruct patients to recognize clinical signs and symptoms of hematologic toxicity, such as infections, fatigue, ecchymosis, and abnormal bleeding, and to notify the physician if they develop. To improve compliance, carbamazepine should be started at a low dose (e.g., 50 mg twice daily) and increased over several weeks to a therapeutic level (200 to 300 mg 4 times a day).

Oxcarbazepine, an analog of carbamazepine, is not associated with blood dyscrasias or hepatic insult and, therefore, may be an alternative for some patients.

Phenytoin is also useful for neuropathic pain, although it is less effective than carbamazepine for trigeminal neuralgia.36,37 Neuropathic pain caused by structural lesions that trigger nerve or root compression can paradoxically increase when phenytoin is administered. Phenytoin has a slow and variable oral absorption, some of which is dependent upon gastrointestinal (GI) motility and transit time. Toxicity includes central nervous system (CNS) effects and cardiac conduction abnormalities. Other side effects are common, including hirsutism, GI and hematologic effects, and gingival hyperplasia.38 Allergies to phenytoin may involve the skin, liver, and bone marrow. There are numerous potential drug interactions, including induction of cytochrome P 450 (CYP450) enzymes, which may accelerate the metabolism of other drugs. Because of such side effects and toxicity, phenytoin is not a first-line drug for neuropathic pain.

The principal non-antiepileptic FDA-approved use of valproic acid is migraine headache, for which it has been shown to reduce the frequency of attacks by about 50%.39 Although there is little published information on the efficacy of valproic acid for neuropathic pain syndromes, based on its mechanism of action, it may be useful alone or in combination with other adjuvant drugs. The FDA now has a black-box warning indicating the potential of birth defects when valproic acid is used for migraine in women of childbearing age. While valproic acid is otherwise generally considered safe for adults, potential side effects include weight gain, hepatic injury, and thrombocytopenia, particularly in children on multiple antiepileptic medications. Divalproex sodium is better tolerated than valproic acid.

Clonazepam may be useful for lancinating radiculopathic and neuropathic pain. The drug has a long half-life (18 to 50 hours), which reduces the risk of inducing an abstinence syndrome on abrupt withdrawal. The major side effects of clonazepam include sedation and cognitive dysfunction, especially in the elderly. Although the risk of organ toxicity is minimal, some clinicians recommend periodic blood cell and liver function tests. Starting doses of 0.5 to 1.0 mg at bedtime are appropriate to reduce the incidence of daytime sedation.

Topiramate was approved for treatment of migraine by the FDA in 2004. Evidence of its effectiveness in painful diabetic neuropathy is mixed, although 1 placebo-controlled trial did find that topiramate reduced pain and body weight more effectively than placebo.40 The drug may be associated with weight loss and cognitive dysfunction.

Lamotrigine has been reported to be useful in the treatment of central pain syndromes, including trigeminal neuralgia.41 However, Cochrane Reviews found it not to be effective.42 Long-term use can lead to Stevens-Johnson syndrome, toxic epidermal necrolysis, and visual blurring.

Antidepressant Medications

The most useful antidepressant medications (ADMs) for pain are serotonin and norepinephrine-reuptake inhibitors (SNRIs). Evidence also supports a role for TCAs and selective serotonin reuptake inhibitors (SSRIs), as well as the norepinephrine-dopamine reuptake inhibitor bupropion and the atypical antidepressant mirtazapine.43

Because SNRIs inhibit the CYP450 enzyme system, they can cause delayed clearance of some other medications, particularly those that use the CYP450 1A2, 2D6, and 3A4 enzymes as metabolic substrates.44

Duloxetine is a serotonergic and noradrenergic reuptake inhibitor with low affinity for other neurotransmitter systems, and it has been shown to be effective for major depressive disorders as well as neuropathic and fibromyalgia pain.45-48 The most common adverse events affect the GI and nervous systems. It should not be used in combination with nonselective monoamine oxidase inhibitors (MAOIs) or CYP450 1A2 inhibitors.46

Several double-blind, randomized, multicenter trials comparing duloxetine with placebo support its use for the treatment of DPN. In one study, duloxetine 60 mg daily or bid appeared superior to placebo, with discontinuations due to adverse events more frequent in the duloxetine 60 mg bid group.49 In another study of types 1 and 2 diabetics with DPN, both 60 and 120 mg daily dosages resulted in statistically significant improvement in pain compared to placebo.50

Duloxetine has also been found to be safe and effective for many symptoms associated with fibromyalgia in patients with or without a major depressive disorder. Women, in particular, appeared to benefit.47,51,52

Venlafaxine is a novel phenylethylamine antidepressant that blocks serotonin and norepinephrine reuptake, although its analgesic actions may be mediated by both an opioid mechanism and adrenergic effects.53 It appears to block serotonin reuptake at low dosages, norepinephrine reuptake at high dosages, and dopamine at very high dosages.44 The drug may be at least as well tolerated as TCAs and more effective for pain than standard doses of SSRIs. Indeed, an initial report suggests that venlafaxine is effective for neuropathic pain.54 Venlafaxine should be started at half of a 37.5 mg tablet twice daily (bid) and titrated weekly to a maximum of 75 mg bid. An extended-release formulation of the drug was effective in relieving pain associated with diabetic neuropathy. The NNT values for the higher dose of venlafaxine ER are comparable with those of the TCAs and gabapentin.55

Venlafaxine may increase the risk of serotonin syndrome when used with MAOIs, TCAs, SSRIs, tramadol, bupropion, and buspirone. It should be used with caution in patients with hypertension or a history of seizures, and should be withdrawn slowly. The most common adverse events include nausea, headache, nervousness, tremor, dry mouth, somnolence, diaphoresis, constipation, and sexual dysfunction.

Milnacipran (Savella), FDA approved in January 2009 for the treatment of fibromyalgia, blocks both serotonin and norepinephrine. It preferentially blocks the reuptake of norepinephrine with higher potency than serotonin. Side effects include itching, sweating and chills, vertigo, headache, GI complaints, orthostatic dizziness, depression, lethargy, hot flashes, and difficulty urinating. Higher doses can exacerbate hypertension.56,57

Suicidality Risks

The FDA has issued black-box warnings for both ACMs and ADMs due to associated risks of suicide.

In 2008, the FDA announced that it would require makers of ACMs to add a warning to their drug labels regarding an increased risk of suicidal thoughts and behaviors. The FDA based its action on the agency’s meta-analysis of 199 clinical trials of 11 ACMs for multiple indications, which showed that patients taking antiepileptics had almost twice the suicidal behavior or thoughts compared to a placebo group (0.37% vs 0.22%).58

The FDA stated that “all patients who are currently taking or starting on any antiepileptic drug for any indication should be monitored for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts, behaviors, or depression.”59

Similarly, in 2004, the FDA requested a black-box warning that states children and adolescents taking antidepressants have an increased risk of suicide. In 2007, this warning was increased to include older patients and reads, in part, “Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.”59 There did not appear to be an increased risk of suicide in adults over the age of 24.

Last updated on: April 29, 2019
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