Nonsteroidal Anti-Inflammatories

NSAIDs are on the first step of the WHO analgesic ladder ( Table 1 ). NSAIDS reduce inflammation by blocking prostaglandin production through the inhibition of cyclooxygenase enzymes, COX-1 and COX-2, in the prostaglandin production pathway. Most anti-inflammatory actions of NSAIDs are attributable to inhibition of COX-2, whereas many of the unwanted side effects are attributable to inhibition of COX-1. Traditional NSAIDs inhibit both COX-1 and COX-2, thereby reducing pain and inflammation but also predisposing to unwanted gastrointestinal (GI) side effects. The cumulative risk for serious adverse GI events increases over time. Risk factors for serious GI events are age, corticosteroid use, high NSAID dose, disability level, and previous NSAID-induced GI symptoms. Medications more selective of COX-2 inhibition such as celecoxib and meloxicam have fewer GI side effects because gastric production of cytoprotective prostacyclin through the COX-1 pathway is preserved. Although these medications have been shown to have fewer GI side effects when compared with traditional NSAIDs, some COX-2 inhibitors are associated with increased cardiovascular risk. Recently, COX-2 inhibitors valdecoxib (Bextra) and rofecoxib (Vioxx) were removed from the US market; Bextra was shown to have increased potential for Stevens Johnson syndrome and increased mortality in patients with coronary artery bypass grafts and Vioxx was shown to have increased overall cardiac mortality. In addition, a 2006 meta-analysis by Singh and colleagues suggested that some nonselective NSAIDs such as diclofenac and ibuprofen also increase the risk of adverse cardiovascular events, such as myocardial infarction. Other nonselective NSAIDs, such as naproxen, have been shown to have fewer adverse cardiovascular effects.

Another significant adverse effect of NSAIDs is renal failure. Caution is therefore advised in the elderly, as this population may have higher risk of GI bleed, cardiovascular disease, and impaired renal function.

Acetaminophen

Acetaminophen is another WHO step 1 analgesic medication commonly used to treat neck pain. The mechanism of action for acetaminophen is not clearly understood but is believed to be secondary to central antipyretic and analgesic actions activated by descending serotonergic pathways. Like NSAIDs, it is also known to inhibit prostaglandin synthesis; however, as only a weak inhibitor of COX-1 and COX-2, it has little anti-inflammatory activity. There has also been some discussion that inhibition of COX-3, a splice variant of COX-1, is involved, but more recent analysis indicates that this interaction is not clinically relevant. Graham suggests that the primary site of action is inhibition of prostaglandin synthesis through production of reactive metabolites by the peroxidase function of COX-2.

The primary concern for acetaminophen is hepatotoxicity. In fact, acetaminophen is the most common cause of acute liver failure in the United States and the United Kingdom, with a trend toward increasing incidence. The maximum recommended dosage of acetaminophen for 24 hours is 4 g in divided doses. However, in 2009, the Food and Drug Administration Advisory Panel recommended decreasing the total daily dosage of acetaminophen to 3250 mg because of this risk ( Table 2 ). In fact, Watkins and colleagues demonstrated that recurrent daily intake of 4 g of acetaminophen in healthy adults was associated with alanine aminotransferase elevations; patients with a history of depression, chronic pain, alcohol use, narcotic use, or who take several acetaminophen-based preparations simultaneously may be at higher risk for hepatotoxicity. It is important to note that acetaminophen has also demonstrated renal toxicity with prolonged use.

Opioids

There are 3 main types of opioid receptors: mu, delta, and kappa. The analgesic and side-effect profile of an opioid depends on how well it binds to a particular receptor. For example, morphine preferentially binds mu-receptors over delta and kappa. Delta-receptor and kappa-receptor agonists have arguably lower abuse potential and side-effect burden than mu-opioid receptor agonists.

Although initially intended for use in the cancer population, opioids are commonly prescribed for chronic noncancer pain, including neck pain, and may be effective for short-term pain relief. When deciding to use opioids to treat neck pain, one must weigh the potential for risk of abuse and dependence versus undertreatment of a patient’s pain. The undertreatment of pain has led to the development of initiatives to increase awareness of and improve pain control. However, some argue that these efforts have led to an increase in opioid adverse drug reactions.

Tolerance, the development of a diminished response to a drug after continued use, should also be considered. Opioid rotation is one strategy for managing tolerance and involves changing from one opioid to another to prevent an otherwise gradual increase in opioid dosing over time. This strategy allows a lower comparative dose secondary to incomplete cross tolerance between opioids. Another strategy to lower tolerance is periodic opiate holidays with restarting of medication at a lower dosage. Although opioid rotations and holidays depend on different factors contributing to an individual’s response to a specific opioid, they remain important strategies to use in the management of chronic neck pain.

When treating neck pain with opiates, it is important to keep in mind the possibility of opioid-induced hyperalgesia (OIH). OIH occurs when treatment with opioids results in a lowering of pain threshold. The clinical picture may be similar to that of opioid tolerance, with worsening pain despite increasing opioid doses. Abnormal pain symptoms such as allodynia may occur concurrently. Clinicians should suspect OIH when opioid treatment becomes less efficacious, particularly in the context of unexplained new pain, diffuse allodynia, or changes in quality of pain compared with that previously observed. The cause of OIH is unknown but is believed to be related to receptor desensitization via uncoupling of the receptor from G-proteins, upregulation of the cAMP pathway, and activation of the N -methyl- d -aspartate (NMDA)-receptor system, as well as descending facilitation. OIH should be considered in patients undergoing neck surgery, as large doses of intraoperative mu-receptor agonists were found to increase postoperative pain and morphine consumption. Treatment strategies for OIH are similar to those for tolerance, and include opioid dose reduction, opioid rotation, and transition to agents with NMDA receptor antagonism.

Tramadol

Although not specifically mentioned, combination medications such as tramadol are considered by the authors to be between step 1 and step 2 of the WHO analgesic ladder. Although the exact mechanism through which patients find relief with tramadol is uncertain, it is known that tramadol has action on both mu-opioid receptor activation, and on serotonin and norepinephrine reuptake inhibition. Because of its mixed mechanism of action, tramadol can be considered for mild-moderate pain before using “weak” opioids. However, in rare instances tramadol has led to abuse and dependence, and it carries warnings about renal failure, seizures, and potential serotonin syndrome when used with other serotonergic medications.

Muscle Relaxants

Skeletal muscle relaxants consist of antispasticity and antispasmodic agents. They are used to treat a variety of conditions from stroke-related spasticity and multiple sclerosis to musculoskeletal conditions such as muscle spasm and mechanical neck pain. Agents classified under antispasticity medications include baclofen, tizanidine, dantrolene, and diazepam. These are classically used for treating muscle hypertonicity and involuntary jerks. Antispasmodic agents, such as cyclobenzaprine, carisoprodol, methocarbamol, chlorzoxazone, and metaxalone, are primarily used to treat musculoskeletal conditions, such as muscle spasm and other myofascial pain. Although antispasmodic agents are often used for prolonged periods, their use in acute musculoskeletal injury ideally should not exceed 3 weeks, as evidence for prolonged use is not established. Although antispasmodic agents are seldom used to manage spasticity, either antispasticity agents or antispasmodic agents can be considered in the treatment of mechanical neck pain.

Efficacy of these medications with regard to spasticity will not be addressed given that musculoskeletal neck pain is the focus of this discussion. In this regard, cyclobenzaprine is the most studied and has been efficacious for various musculoskeletal conditions. Cyclobenzaprine was found to be significantly better in treating neck and lumbar pain compared with diazepam. Chou and colleagues performed a systematic review of existing literature and concluded that there is fair evidence in favor of cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine compared with placebo for patients with musculoskeletal neck pain, but limited or inconsistent data for metaxalone, methocarbamol, chlorzoxazone, baclofen, or dantrolene. However, there was insufficient evidence to determine safety or efficacy for these medications, and as such, treatment recommendations for these medications will depend on patient response, side effects, and cost. Tizanidine and cyclobenzaprine may benefit patients with insomnia caused by severe muscle spasms, whereas methocarbamol and metaxalone are less sedating but with weaker evidence of clinical effectiveness. Common adverse effects of all muscle relaxants are dizziness and drowsiness. Dantrolene, and to a lesser degree chlorzoxazone, have been associated with rare but serious hepatotoxicity.

One particular muscle relaxant that deserves special attention is carisoprodol. Although carisoprodol has a poorly understood mechanism of action, its effects are theorized to be related to the sedative properties of its metabolite, meprobamate. Unfortunately, meprobamate is known historically to have a high potential for dependence, abuse, and withdrawal. A literature review by Boothby and colleagues produced little evidence to support the use of carisoprodol in pain control. It also showed that patients, especially those with a history of previous substance abuse, are more likely to abuse this drug. As there is little evidence to support efficacy and ample evidence to support abuse, clinicians should seriously consider the risk-benefit ratio before prescribing carisoprodol. In instances of withdrawal, other sedatives may be considered to alleviate symptoms.

Muscle Relaxants

Skeletal muscle relaxants consist of antispasticity and antispasmodic agents. They are used to treat a variety of conditions from stroke-related spasticity and multiple sclerosis to musculoskeletal conditions such as muscle spasm and mechanical neck pain. Agents classified under antispasticity medications include baclofen, tizanidine, dantrolene, and diazepam. These are classically used for treating muscle hypertonicity and involuntary jerks. Antispasmodic agents, such as cyclobenzaprine, carisoprodol, methocarbamol, chlorzoxazone, and metaxalone, are primarily used to treat musculoskeletal conditions, such as muscle spasm and other myofascial pain. Although antispasmodic agents are often used for prolonged periods, their use in acute musculoskeletal injury ideally should not exceed 3 weeks, as evidence for prolonged use is not established. Although antispasmodic agents are seldom used to manage spasticity, either antispasticity agents or antispasmodic agents can be considered in the treatment of mechanical neck pain.

Efficacy of these medications with regard to spasticity will not be addressed given that musculoskeletal neck pain is the focus of this discussion. In this regard, cyclobenzaprine is the most studied and has been efficacious for various musculoskeletal conditions. Cyclobenzaprine was found to be significantly better in treating neck and lumbar pain compared with diazepam. Chou and colleagues performed a systematic review of existing literature and concluded that there is fair evidence in favor of cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine compared with placebo for patients with musculoskeletal neck pain, but limited or inconsistent data for metaxalone, methocarbamol, chlorzoxazone, baclofen, or dantrolene. However, there was insufficient evidence to determine safety or efficacy for these medications, and as such, treatment recommendations for these medications will depend on patient response, side effects, and cost. Tizanidine and cyclobenzaprine may benefit patients with insomnia caused by severe muscle spasms, whereas methocarbamol and metaxalone are less sedating but with weaker evidence of clinical effectiveness. Common adverse effects of all muscle relaxants are dizziness and drowsiness. Dantrolene, and to a lesser degree chlorzoxazone, have been associated with rare but serious hepatotoxicity.

One particular muscle relaxant that deserves special attention is carisoprodol. Although carisoprodol has a poorly understood mechanism of action, its effects are theorized to be related to the sedative properties of its metabolite, meprobamate. Unfortunately, meprobamate is known historically to have a high potential for dependence, abuse, and withdrawal. A literature review by Boothby and colleagues produced little evidence to support the use of carisoprodol in pain control. It also showed that patients, especially those with a history of previous substance abuse, are more likely to abuse this drug. As there is little evidence to support efficacy and ample evidence to support abuse, clinicians should seriously consider the risk-benefit ratio before prescribing carisoprodol. In instances of withdrawal, other sedatives may be considered to alleviate symptoms.

Trigger Point Injections

Local injections allow placement of medication directly at the location where its action is most desired. Commonly used medications are local anesthetics, corticosteroids, and botulinum toxin. Injection of lidocaine into myofascial trigger points has been shown to improve visual analog pain scores and quality of life. One study found that intramuscular injection of lidocaine for chronic mechanical neck pain was superior to placebo or dry needling in the short term. However, another recent study comparing local anesthetic to dry needling of trigger points found statistically significant improvements in visual analog pain scale, cervical range of motion, and Beck Depression Inventory scores with both treatments. In addition, a prospective randomized evaluation of treatments for myofascial trigger points argues that dry needling provides as much relief as when a local anesthetic or corticosteroid is injected. Given this uncertainty and lack of consensus in the literature, one should weigh the risks and benefits when using trigger point injections for myofascial pain.

Botulinum toxin is another injectable agent used to treat mechanical and myofascial pain. It works by inhibiting presynaptic acetylcholine release. Although one study showed that injection of botulinum toxin improves visual analog pain scores and quality of life measures compared with dry needling in myofascial disorders, it has not been shown to be superior to saline injection for chronic mechanical neck disorders. Injection of botulinum toxin was also comparable to local anesthetic in terms of duration and degree of pain relief, function, and patient satisfaction. In a review of 5 clinical trials, only one study concluded that botulinum toxin was effective, whereas the others did not support its utility in reducing trigger point pain. Still, some consider injection of botulinum toxin as a second-line treatment when patients fail to achieve adequate relief with other modalities. Other important considerations with botulinum toxin are its cost and risk of dysphagia, particularly when injecting in the cervical regions.