Neck Pain in Adults _________________________________________________________________________
Antiepileptic Drugs Antiepileptic drugs are diverse, but pregabalin and gabapentin are the only widely studied agents in chronic low back pain. As with antidepressants, few neck pain studies are available and chronic low back pain outcomes are used to inform decisions. Pregabalin and gabapentin are widely recommended first-line agents in neuropathic pain disorders, such as painful diabetic neuropathies and postherpetic neuralgia [70]. Analgesic, anxiolytic, and anticonvulsant effects arise from binding to alpha-2/delta-1 subunits of calcium channels, highly expressed in brainstem structures where descending pain modulatory pathways originate and a likely key analgesic target of pregabalin/gabapentin [68]. Pregabalin has greater binding affinity and greater analgesic potency in neuropathic pain than gabapentin. Pregabalin also has more rapid absorption, greater bioavailability, and a linear dose-response [68]. The dosage of pregabalin in pain treatment is 300–600 mg/ day in divided doses. Gabapentin is used at 1,200–3,600 mg/day in three divided doses. Both can be initiated at 10% the maximum dose, increased every three to four days [71]. Pregabalin 600 mg/day has greater efficacy than 300 mg/day [70]. Pregabalin/gabapentin is generally well tolerated. The adverse effects most common with pregabalin are dizziness, somnolence, dry mouth, edema, and blurred vision; with gabapentin, common adverse effects include dizziness and somnolence (>20% of patients), confusion, and peripheral edema [68]. Adverse effects increase with pregabalin dose but do not appear to be age-related. In patients 65 years of age and older, titration to the lowest effective dose may help minimize adverse effects. Absence of known drug interactions with pregabalin/ gabapentin increases safety in patients requiring polypharmacy [153]. Gabapentinoid efficacy in chronic spine-related pain is inconsistent. An uncontrolled study compared pregabalin monotherapy, pregabalin add-on therapy, and non-pregabalin therapy under “real-world” primary care conditions in 1,351 patients with chronic painful cervical (13%) or lumbosacral (87%) radiculopathy [154]. Pregabalin groups received 190 mg/day (mean). At 12 weeks, pain intensity reduction ≥50% was attained by 63%, 56%, and 33% of patients in pregabalin, pregabalin add-on, and non-pregabalin groups, respectively. Differences in pain reduction were significant by week 4. Improvements in sleep disturbances, depression, anxiety, and quality of life showed large effect sizes in pregabalin groups and moderate effect sizes in the non-pregabalin group [154]. The authors noted non-pregabalin patients received NSAIDs (67%) or acetaminophen (37%) rather than tramadol
but norepinephrine activity accounts for analgesic effects. In contrast, SSRI antidepressants have negligible norepinephrine activity and minimal analgesic efficacy. Unlike TCAs, SNRIs require antidepressant doses for analgesia, especially venlafaxine, which only inhibits serotonin reuptake at lower doses (<200 mg/day) [147]. Duloxetine 60–120 mg/ day is used for pain, with doses <60 mg/day ineffective [71]. Several placebo-controlled trials have evaluated duloxetine in chronic low back pain without radiculopathy or stenosis. Outcomes from four of these studies were pooled; 12 to 14 weeks of duloxetine led to pain reduction ≥30% in 60% (versus 48% with placebo) and ≥50% in 49% (versus 35% with placebo). Analgesic response to duloxetine surpassed placebo by 13% on both pain outcomes [148]. Another study of different doses found duloxetine 20 mg, 60 mg, and 120 mg no different from placebo at week 13, and noted a 24% dropout rate from side effects with duloxetine 120 mg [149]. Duloxetine doses higher than 60 mg daily have not consistently shown benefit in clinical trials [147]. With duloxetine in chronic pain, analgesic effects accounted for 91% of pain reduction in patients screened for depression, which shifted over time to antidepressant effects in patients with comorbid depression. The authors noted the mutually reinforcing relationship between pain and depression makes it plausible that alleviating depression can reduce pain symptoms [150]. Duloxetine was less effective in isolated chronic low back pain than in patients with two or more painful sites. Multiple pain sites may better reflect CNS alterations that amplify pain perception, and suggest duloxetine is more effective in centralized chronic pain [148]. Milnacipran, another SNRI, after six weeks was no different from placebo in pain reduction in chronic low back pain with
a neuropathic component [151]. Antidepressant Adverse Effects
TCA side effects are intolerable for some patients, and low- dose (10 mg/day) initiation with gradual increase to 75 mg/ day is suggested [71]. TCAs should be used cautiously in elderly patients due to greater risks of postural hypotension, impaired cognition, and falls and should be avoided in patients with a history of cardiovascular disease [68; 147]. In placebo-controlled pain studies, desipramine and venlafaxine had the highest overall rates of adverse effects. Desipramine, milnacipran, venlafaxine, and duloxetine had highest dropout from side effects, suggesting greater severity and unpleasant perception. Adverse effects associated with duloxetine (e.g., nausea, constipation, dry mouth, hyperhidrosis) differed somewhat from amitriptyline (e.g., dry mouth, thirst, constipation, headache, weight gain, blurred vision, palpitations) [152].
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