Neck Pain in Adults _________________________________________________________________________
Another review of NSAIDs in spine pain found two neck pain studies. One involved intravenous NSAIDs, but the other study found greater pain reduction with indomethacin and piroxicam over placebo, and no difference between NSAIDs [47]. NSAIDs inhibit cyclooxygenase-1 and -2 (COX-1 and COX-2), enzymes that convert arachidonic acid to pro-inflammatory prostanoids. COX-2 inhibition reduces inflammation and pain. Prostanoids also play key roles in maintaining normal physiologic processes; their inhibition accounts for the adverse effects of NSAIDs [131; 132]. COX-1 inhibition suppresses prostaglandins that protect the gastric mucosa and thromboxanes that promote platelet aggregation. COX-2 inhibition suppresses prostacyclins in vascular endothelium that inhibit platelet aggregation [133]. Thus, serious or fatal GI, cardiovascular, or renal adverse effects can result from NSAIDs use [132]. In 1997, 16,500 deaths from upper GI bleeding/perforation were linked to NSAIDs [134; 135]. This prompted introduction of COX-2-selective NSAIDs to reduce GI risks, which became linked to cardiovascular adverse effects. The view emerged that COX-2 selective NSAIDs had greater risk of cardiovascular toxicity and lower risk of GI toxicity than traditional NSAIDs. Greater accrual of patient outcomes demonstrated all NSAIDs carry GI and cardiovascular risks [131; 136; 137; 138]. Celecoxib has the least GI toxicity but high, dose-related cardiovascular risk. Naproxen has the best cardiovascular safety, but greatest GI toxicity [138]. Concurrent NSAID and selective serotonin reuptake inhibitor (SSRI) use increases upper GI bleeding risks [139; 140]. Adding a proton pump inhibitor or switching NSAIDs to celecoxib is recommended to mitigate upper GI risks [141]. Despite greater awareness, NSAIDs cause 7,000 to 10,000 GI hemorrhage fatalities annually [142]. All NSAIDs increase risks of fatal and non-fatal cardiovascular and cerebrovascular events and renal failure, especially in elderly patients. Serious adverse effects can occur within one month of regular therapy. Long-term NSAID use is not recommended, and NSAIDs should be used at the lowest effective dose for the shortest duration possible [103; 133; 143]. Given the risk profile, clinicians should reconsider using NSAIDs for pain and limit their use to pain with inflammation [144]. Antidepressants Noradrenergic projections form a key component of descending pain inhibition pathways. Impaired descending pain inhibition can facilitate and maintain chronic pain. Drugs that inhibit norepinephrine reuptake can enhance spinal noradrenergic efficiency to reduce chronic pain, including some antidepressants and the opioids tramadol and tapentadol [69; 122].
Tricyclic antidepressants (TCAs) and selective serotonin/ norepinephrine reuptake inhibitors (SNRIs) are recommended first-line options in chronic neuropathic pain disorders and in chronic pain with a neuropathic component [67; 69; 71]. Tricyclic Antidepressants The first antidepressants used in pain treatment, TCAs may also produce analgesia by blocking NMDA-induced hyperalgesia, voltage-gated sodium channels, and delta-opioid receptor interaction [145; 146; 147]. Amitriptyline is the most studied, endorsed, and prescribed TCA in chronic pain, and some evidence suggests it may be the most effective analgesic antidepressant [68; 70; 71; 79]. Other TCAs (e.g., nortriptyline, desipramine) are better tolerated but lack the evidence base of amitriptyline. Analgesic effects are independent of antidepressant effect, and analgesic dosing is 20% to 33% of antidepressant doses [147]. SNRIs Duloxetine and venlafaxine are the most-studied SNRIs in chronic pain, with duloxetine the most widely endorsed agent [79]. SNRIs inhibit reuptake of serotonin and norepinephrine, 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].
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