Industrial Medicine and Acute Musculoskeletal Rehabilitation. 2. Medications for the Treatment of Acute Musculoskeletal Pain

2.1 Educational Activity: To differentiate the mechanisms of action and side effects of commonly prescribed “muscle relaxants” to consider in treating this worker’s neck pain 

SKELETAL MUSCLE RELAXANTS (SMRs) are often prescribed for the treatment of acute musculoskeletal pain. The term “muscle relaxant” is a misnomer, because most medications in this class have little or no direct action on the contractile mechanisms of striated skeletal muscle. Because many of these medications were initially used as treatment for nonspecific back pain typically labeled as a strain, sprain, or mechanical back pain, these drugs were considered muscle relaxants. It is unclear whether these medications actually decrease painful muscle spasm or if they exert other effects.1 This finding is in contrast to agents used to decrease spasticity associated with upper motoneuron lesions. Agents used in the treatment of both neurogenic spasticity and local muscle “spasm,” such include medications as tizanidine (Zanaflex), baclofen (Lioresal), and diazepam (Valium).1 Antispasmodic agents, which are generally classified as muscle relaxants, are listed in table 1.

Table 1. Antispasmotic Medications

	Category	Medication (Product) Manufacturer
	Antihistamines	Orphenadrine (Norflex) 3M
	Central nervous system depressants	Chlorzoxazone (Parafon, Forte DSC; Paraflex) Ortho-McNeil Metaxalone (Skelaxin) King Methacarbamol (Robaxin) Schwarz Carisoprodol (Soma) Wallace
	Central alpha2-adrenergic agonists	Tizanidine (Zanaflex) Elan
	Tricyclic antidepressant agents	Cyclobenzaprine (Flexeril) McNeil
	γ-aminobutyric acid agonists	Diazepam (Valium) Roche Baclofen (Lioresal) Novartis Other benzodiazepines

These medications have various primary sites of action, and consequently they differ in their drug actions and side effects. However, all can cause significant drowsiness. The drug manufacturers warn patients that activities such as driving or operating machinery may be impaired while they are taking these medications. This is an important consideration in the case of the injured Department of Transportation worker, who must be able to drive and/or function on the job in heavy, high-speed traffic. Also, these drugs are hepatically metabolized and renally excreted and must be used cautiously in patients with liver or kidney disease.

Three commonly prescribed agents used as SMRs include metaxalone, cyclobenzaprine, and carisoprodol. Each SMR has different mechanisms of action and side-effect profiles, although older studies have not shown any particular SMR to have superior efficacy. Medications that are approved for treatment of spasticity and are sometimes used to treat musculoskeletal pain include baclofen and tizanidine.

Metaxalone was initially introduced in 1962. Its exact mechanism of action is unknown; it is thought to act by depressing polysynaptic spinal reflexes. Studies2 have shown a low rate of side effects with no reports of sedation. Double-blind placebo studies2 from the 1960s and 1970s showed positive effects in reducing back pain with no reports in the literature of dangerous side effects or safety concerns.

Cyclobenzaprine is structurally similar to tricyclic antidepressants (TCAs) and was first studied as an antidepressant with regard to efficacy and safety.2 The exact mechanism of action is unknown, but it is presumed to work at the level of the brainstem or higher with a generalized sedative effect.2 Studies have repeatedly shown its superiority over placebo3 and efficacy at least comparable to diazepam.2 It is also more effective when used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) than are NSAIDs alone.4 Its chemical similarity to TCAs explains its main side effects of sedation, lethargy, and other anticholinergic effects. There are case reports of adverse reaction of cyclobenzaprine in combination with alcohol, tramadol, droperidol, and other multiple drug interactions.2

Carisoprodol has been in use for decades. Although its exact mechanism is not clear, it may be related to its sedative effects. Some studies2 suggest blockage of interneuronal activity in the descending reticular formation and spinal cord. Although carisoprodol has been shown to be more effective than placebo, comparison with other SMRs has not shown any reproducible differences. More importantly, there are serious safety concerns related to its active metabolite, meprobamate, which is a schedule IV controlled substance. There are multiple reports2 of abuse and cases of impaired driving associated with carisoprodol. Interestingly, a questionnaire probing prescribing practices showed that a low percentage of physicians recognized the abuse potential and had an understanding of the active metabolite, despite this being a heavily prescribed drug.2

Baclofen is a chemical analog of γ-aminobutyric acid that acts by inhibiting synaptic transmission in the spinal cord.1 It is mainly used in the treatment of neurogenic spasticity with efficacy similar to diazepam, dantrolene, and tizanidine. It generally causes less sedation but may lead to increased weakness. Baclofen is not generally used as therapy for acute paravertebral muscle spasm.1

Tizanidine is approved for the treatment of spasticity and is also used to treat pain and “spasm” from musculoskeletal conditions. It is an agonist at α2-adrenergic receptor sites and presumably reduces spasticity by increased presynaptic inhibition of motoneurons.1 Several studies1 have shown its efficacy for patients with musculoskeletal back pain with side effects similar to those of other SMRs and drowsiness as the primary reason for discontinuing the medication. There is a case report1 of hypotension when used in combination with an antihypertensive medication, possibly due to its chemical similarity to clonidine.

In the case of the highway worker with presumed “muscle spasm” and pain, the choice of SMR for pain relief is important. Side effects and abuse potential should be considered before prescribing this class of medication. Shorter duration of treatment is generally recommended to limit potential of side effects and/or abuse.1, 2

2.2 Educational Activity: To discuss the use of NSAIDs in the treatment of neck pain in this highway worker 

NSAIDs are commonly prescribed medications. Since 1991, 7 new NSAIDs have entered the U.S. market. These are listed in table 2.

Table 2. Recently Approved NSAIDs

	Medication (trade name)	Manufacturer	Year FDA Approved
	Ketorolac (Toradol)	Syntex	1991
	Diclofenac potassium (Cataflam)	Novartis	1993
	Bromfenac (Duract)	Wyeth-Ayerst	1997 (withdrawn 1998)
	Celecoxib (Celebrex)	Searle	1998
	Refecoxib (Vioxx)	Merck	1999 (withdrawn 2004)
	Meloxicam (Mobic)	Boehringer Ingleheim/Abbott	2000
	Valdecoxib (Bextra)	Searle	2001 (withdrawn 2005)

NOTE. Data from Ridgway.14

Drug manufacturers are required to show analgesic efficacy for each of the agents. The models most commonly used to obtain approval from the U.S. Food and Drug Administration (FDA) are dental pain, postsurgical pain, dysmenorrheal, and postpartum cramps. Although some of these agents have FDA approval for the treatment of rheumatoid arthritis and osteoarthritis, some are also approved for the treatment of acute pain. Note that several of these medications have been pulled from the market because of the postmarketing identification of side effects. Bromfenac was withdrawn because of liver toxicity. Rofecoxib and valdecoxib were withdrawn because of cardiovascular events. The FDA also recommended stronger warnings for all NSAIDs because of gastrointestinal (GI) toxicity and increased risk of cardiovascular events. This recommendation included conventional NSAIDs, because little information existed regarding their cardiovascular risks.5, 6

Although there is no evidence to suggest superior efficacy of one NSAID over another, individual patients may respond differently to different medications. Conventional NSAIDs act by inhibiting cyclooxygenase (COX)–2 and the pathologic responses to pain and inflammation. In the GI tract, they also inhibit COX-1 activity, decrease prostaglandins, and increase the risk of GI side effects such as life-threatening bleeding. Conventional NSAIDs show dose-dependent side effects, which may limit their use in elderly people or other patients at high risk. Additional side effects include renal dysfunction and platelet inhibition. The COX-2–specific agents (celecoxib) have a decreased incidence of GI toxicity,7 but increased costs and cardiovascular risks may limit their utility in the elderly and in those with cardiovascular risk factors. COX-2–selective agents (etodolac, meloxicam) have a decreased risk of clinically significant GI side effects compared with other NSAIDs.8, 9 Etodolac has increased COX-2 selectivity compared with celecoxib and meloxicam, but the cardiovascular risks are unknown. Whether a patient is on a COX-2–selective or –specific agent, those agents’ GI protectivity may be compromised by concomitant use of even low-dose aspirin, and renal side effects are not decreased.10

A medication recently approved by the FDA for the treatment of osteoarthritis is flavocoxid (Limbrel). This product is a blend of natural ingredients from phytochemical food source materials. It is presumed to have action on COX and lipoxygenase pathways, limiting prostaglandins and leukotrienes. It is not a COX-2–specific or –selective agent, and its ingredients are generally regarded as safe according to the FDA. To our knowledge, there is no literature available at the time of this writing to suggest efficacy in the treatment of acute musculoskeletal pain.

2.3 Educational Activity: To outline a treatment algorithm for the medication management of acute pain in a 40-year-old home improvement warehouse store worker who fell off a ladder, injuring his foot and ankle 

Physicians most often recommend or prescribe oral medications for the treatment of acute musculoskeletal pain. Acute pain generally does not require long-term use of analgesics. Much of the literature on oral analgesics defines the efficacy of a specific medication as the proportion of patients who need to take that particular drug to experience a least a 50% reduction in pain when compared with placebo. The number needed to treat (NNT) is a concept that refers to the number of patients who have to use the treatment for 1 patient to have a benefit. A lower NNT is better. Other measures of pain relief include a visual analog scale, with a meaningful analgesia effect of 13mm on a 100-mm scale.11

Acetaminophen is a unique medication without a clearly defined mechanism of action related to analgesia. It has little or no anti-inflammatory effects. It also has an excellent safety profile with the exception of liver toxicity at doses exceeding 4000mg daily. An increased GI ulceration risk is not supported by the current literature. Direct comparison studies between acetaminophen (1000-mg dose) and NSAIDs show equivalent analgesia in some settings (orthopedic surgery, tension headache) and NSAID superiority in others (dental and menstrual pain).11 Acetaminophen remains a good initial choice for most mild to moderate acute pain, with equivalent analgesia to aspirin but a better safety profile.

NSAIDs remain excellent analgesics for the treatment of acute pain. As noted above, some study models have shown NSAIDs’ superiority to acetaminophen and equality to narcotics for certain types of pain. Whether this means they are superior for acute pain treatment in all people, such as the patient discussed, has yet to be proven. It is often the dose-dependent side effects that limit their usefulness. Epidemiologic studies support the use of ibuprofen at 400mg per dose when first choosing NSAIDs.11 At 800 to 1200mg a day, ibuprofen has an excellent safety profile that is not significantly different from placebo. Higher doses are used for anti-inflammatory effects and may provide better analgesia, but they are associated with increased risk of side effects.11 Histamine2 blockers, proton pump inhibitors, and misoprostol have been shown to reduce the risk of duodenal ulcers with daily NSAID use, but only misoprostol has been shown to reduce the risk of GI perforation and bleeding.11 However, because the NNT is relatively high (264 patients), it is likely that misoprostol would only be necessary in high-risk patients.11 A meta-analysis of the COX-2 inhibitor celecoxib showed fair to good efficacy for postsurgical pain but overall inconsistent evidence to warrant its routine use in those without a history of GI bleeding.11

Opioids are potent and appropriate analgesics for acute moderate to severe pain, although their use in chronic nonmalignant pain conditions does not have universal consensus. There is no substantial evidence to support the claim that any particular opioid has greater efficacy or fewer side effects than equipotent doses of morphine. The usual treatment of acute pain is with codeine, propoxyphene, hydrocodone, and oxycodone. Studies have indicated that combination therapy with acetaminophen or ibuprofen is highly effective for treatment of acute pain.11 Codeine is a prodrug that depends on cytochrome P450 metabolism to convert to morphine for its analgesic effect. Up to 10% of the white population lacks this enzyme, and this may explain its poor efficacy in meta-analyses addressing acute postsurgical and dental pain. Propoxyphene provides little additional analgesia to acetaminophen alone and is associated with significant adverse side effects.11 For this reason, it cannot be recommended for routine use for the treatment of acute pain such as for the patient discussed.

Tramadol (Ultram) is a synthetic analog of codeine. It is a central analgesic with a low affinity for opioid receptors; however, its primary metabolite shows a higher affinity for opioid receptors than the parent drug. Moreover, the analgesic action of tramadol is only partially inhibited by the opioid antagonist naloxone, which suggests the existence of another mechanism of action. This hypothesis was confirmed by the discovery of monoaminergic activity that inhibits norepinephrine and serotonin reuptake, contributing to the analgesic action. Tramadol should not be administered to patients receiving monoamine oxidase inhibitors, and cotreatment with TCAs and selective serotonin reuptake inhibitors should be undertaken with caution to avoid serotonin syndrome and increased risk of seizure. Tramadol has pharmacologic properties that may make it less likely to lead to dependence. It may be of value in treating pain conditions where treatment with stronger opioids is not required. Others11 report side effects and a lack of efficacy, both of which limit its usefulness. Additional preparations are 325mg of acetaminophen with 37.5mg of tramadol (Ultracet) and an extended-release preparation (Ultram ER).

Options for the treatment of acute ankle pain after a fall off a ladder thus can be summarized as shown in table 3.

Table 3. Treatment Options for Acute Ankle Pain

	Treatment	Comment
	Acetaminophen	1000mg up to 4 times daily
	Acetaminophen plus NSAID	Ibuprofen 400mg every 4–6h
	Combination therapy	Opioid or tramadol with acetaminophen and/or ibuprofen
	Prescription NSAID	For anti-inflammatory effects as needed
	GI protectant	As needed for higher-risk patients
	COX-2 NSAID	Reserved for elderly or high-risk patients

2.4 Educational Activity: To identify the rationale for the use of topical analgesics in the treatment of lateral epicondylitis in a 50-year-old secretary 

Alternative delivery systems such as topical preparations have been developed to try to minimize the adverse effects of NSAIDs. When NSAIDs are applied topically, there is a high concentration in the dermis and muscle levels at least equivalent to systemic administration. There is penetration into synovial fluid, but it is unclear if this is facilitated by systemic circulation. Several studies12 have addressed the efficacy of topical analgesics, including a study on musculoskeletal and soft-tissue injuries. Each study reported efficacy of topical NSAIDs, whether it was by gel, spray, or patch. Most drug reactions were local cutaneous reactions. GI effects were less common but were found to be more likely to occur in those who had GI side effects from oral NSAIDs.

Topical opioid administration has recently been used for the local treatment of painful ulcers and skin lesions. Factors determining bioavailability after application and the potential for cutaneous side effects associated with histamine release need to be evaluated.12 To our knowledge, there are no studies addressing the use of topical opioids for acute musculoskeletal pain. Delivery systems that minimize systemic uptake would also be beneficial to minimize central nervous system side effects.

Capsaicin—a natural constituent in red chili peppers—may induce analgesia via desensitization from substance P and calcitonin gene–related peptide release. Capsaicin has been found to activate a family of thermosensitive vanilloid receptors. Several studies have reported benefit in postherpetic neuralgia, postmastectomy pain, trigeminal neuralgia, cluster headache, osteoarthritis, and other conditions. Whereas pain relief is widely observed, the degree is often modest, and capsaicin is usually reserved for use as an adjunct treatment. Further, side effects, such as burning pain in the initial treatment period, are often difficult for patients to tolerate; such pain has been reported in clinical studies as a common reason for patient drop-out.12 Compliance may also be an issue because of the delay between onset of treatment and observation of therapeutic benefit. For acute musculoskeletal pain, capsaicin likely is not a good treatment option.

Topical formulations of local anesthetics such as the 5% lidocaine patch (Lidoderm) may be an effective alternative to systemic treatment, but most studies have focused on chronic pain conditions. Studies12 on postherpetic neuralgia showed efficacy for treatment of pain with no systemic side effects. Although the use of the 5% lidocaine patch in professional athletes with soft-tissue pain has been reported,13 there is a paucity of published evidence regarding its use in the treatment of acute musculoskeletal pain.

Multiple other classes of medication have been developed, including topical doxepin, glutamate receptor antagonists, α-adrenergic agonists, adenosine, cannabinoids, neostigmine (cholinesterase inhibitor), and gabapentin. These have been studied in animal models and various chronic pain models12 but have not gained acceptance in the treatment of acute pain.