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Cyclobenzaprine: a new look at an old pharmacological agent Expert Rev. Clin. Pharmacol. 2(3), 255–263 (2009)

Nevio Cimolai Department of Pathology and Laboratory Medicine, Children’s and Women’s Centre of British Columbia, Vancouver, BC V6H 3V4, Canada Tel.: +1 604 271 9321 Fax: +1 604 271 9321 [email protected]

Cyclobenzaprine is a tricyclic pharmacologic agent that has enjoyed considerable use since its availability. Most clinical usages have focused on the muscle relaxant properties, the mechanism of action being more recently redefined. Higher orders of the CNS are, nevertheless, affected, and the latter contributes to the spectrum of proclaimed side effects that are otherwise largely anticholinergic in nature. Cyclobenzaprine has a reasonable safety profile and overdoses are not as problematic as those for accepted tricyclic psychotherapeutic agents. Clinical studies have given supportive, albeit not conclusive, evidence for treatment roles in the short-term management of acute neck and back pain, and fibromyalgia. Further and more exacting science is warranted to explore the value of this drug in other neurological and psychiatric contexts. Keywords : back pain • cyclobenzaprine • fibromyalgia • muscle relaxant • toxicity

Cyclobenzaprine, initially marketed under the trade name Flexeril™, has been available for human use since 1977 [1] . Few publications identify cyclobenzaprine contemporaneously as evidenced by cyclobenzaprine being cited only ten  times over the last 2 years in the PubMed scientific database. Nevertheless, the drug continues to enjoy modest use; in 2003, for example, approximately 300,000 prescriptions for generic cyclobenzaprine were made in Canada (population at the time: 31.5 million) [2] . Despite the latter, however, cyclobenzaprine has lost its place in the top 100 generic prescription drugs sold in Canada over the period of 2003–2007 [2,3] . Given its relative safety and tolerability, this drug will continue to be prescribed. The spectrum of its use deserves review and the potential for furthering of this spectrum remains. General considerations

Early studies of cyclobenzaprine use assessed this drug for potential mood-altering properties, such as depression, and this was initially of promise, given that cyclobenzaprine differs from amitriptyline by only one double bond. Eventually, most subsequent studies focused on the drug’s muscle relaxant properties. As such, this pharmacological agent was classified as an antispasmodic skeletal muscle relaxant www.expert-reviews.com

10.1586/ECP.09.5

with many properties akin to benzodiazepines, carisoprodol, metaxalone, chlorzoxazone, methocarbamol, tizanidine and orphenadrine [4] . The antispasmodic quality of cyclobenzaprine appears to apply best to focal muscular disturbances [5,6] . The pharmacological agents listed as potential muscle relaxants are many but some have chosen to distinguish those that give rise to an antispasmodic effect from those that have an antispastic effect [7,8] . The latter include agents such as dantrolene, baclofen or gabapentin. One study has particularly assessed cyclobenzaprine (60 mg/day in divided doses) and placebo in a double-blinded crossover trial for 2 weeks among patients with spasticity as a result of either CNS or PNS disorders; there was no significant difference [9] . Most assessments of cyclobenzaprine include three-times a day dosing, although some have used the drug as a single night-time dose owing to its sedative effect. A recently marketed oral, extended-release form (Amrix®) in the USA has employed 15 or 30 mg units [10] . Muscle relaxant use in the USA has been reviewed recently and is considerable, as estimated by the findings in which the 1-month prevalence was 1% [11] . Muscle relaxants were more often used in the age group of 40–59 years, although 0.77% of those aged over 60 years reported use. The latter use occurred for both acute and chronic medical

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illnesses. Despite the widespread practice, some have suggested that cyclobenzaprine is not an appropriate medication for geriatric patients [12] . Metabolism, excretion & kinetics

Pharmacokinetic assessments find 30–55% bioavailability after a 5-mg dose in healthy young volunteers [13,14] . Peak plasma levels reach approximately 5–35 ng/ml after 4 h, and these levels are not greatly influenced with 5-, 10- or 20-mg doses [15] . Half-life in the blood approaches 18 h [13] and linear pharmacokinetics is applicable. Cyclobenzaprine is highly protein bound [16] . Accumulation occurs after three times a day dosing and increased levels occur in those with hepatic insufficiency and among elderly patients. Very little unchanged drug is excreted in the urine; approximately 10–20% of the drug is excreted in the urine as a glucuronide conjugate [17,18] . Urinary excretion is greater when the drug is administered orally in contrast to parenteral administration [14] . The kinetics of a daily extended-release formulation in comparison to three-times a day dosing has been assessed recently and a relative consistency of plasma concentrations has been demonstrated with the former [19] . Despite the prolonged half-life, the clinical duration of action is usually 4–6 h [20] , although some patients experience more prolonged clinical or subclinical effects. It is proposed that there is a first-pass metabolic modulation after gut absorption and liver processing [14] . The drug is distributed widely and enterohepatic circulation occurs. Oxidative metabolism and conjugation, as well as N-demethylation by cytochrome P450 isoenzymes, takes place in the liver [13,21] . PA2 and 2D6 isoforms and, to a lesser degree, the CYP3A4 isoforms are the main proteins to factor in the latter [10] . Whereas animal models have been used to study cyclo­benzaprine metabolism, the metabolites may be considerably different and varied in contrast to humans (e.g., in rats or dogs)  [18,22–24] . Cyclobenzaprine inhibits aldehyde oxidase activity [25] . Historically, the presence of cyclobenzaprine and its metabolites interfere with amitriptyline assays [26] . Mechanism of action

The pharmacological mechanisms of cyclobenzaprine activity have not been studied in humans in any great detail and the mechanism of action has largely been gleaned from a variety of animal neurophysiological models. At very early stages it was believed that cyclobenzaprine exerted a CNS effect and that neuro­muscular junction or direct skeletal muscle activity was spared  [1] . Cyclobenzaprine gives rise to clinical anticholinergic effects and sinus tachycardia [27] . On the rabbit heart in vitro, it blocks cholinergic receptors and augments both norepinephrine and antihistamines, much like other tricyclic agents of its kind [28] . Clinical studies of 2.5-, 5- and 10-mg dosing in adults, however, found minimal elevation of heart rate and no change in blood pressure [20,29] . Elsewhere, the drug antagonizes reserpine but, again, potentiates norepinephrine [27] . Share, Barnes and colleagues conducted much of the early published neurophysiological study [30–36] . In a variety of animal models, activity appeared to occur mainly at a supra­spinal level, 256

although minimal action on the spinal cord could be ascertained. The supraspinal effects were localized to the brainstem, whereby efferent g and a motor neuron activities were subsequently diminished. These actions were thought to be mediated by noradrenergic coeruleus–spinal or reticulospinal pathways [30,37] . Tachyphylaxis to these effects does not seem to occur [35] . Ultimately, a depression of the activity of spinal cord interneurons occurs. The locus coeruleus was considered a key focus for cyclobenzaprine effects  [38] , but others cautioned against such a simple answer given the variable effects of cyclobenzaprine on locus coeruleus cells in vitro [39] . Nevertheless, cyclobenzaprine was presumed to first exert its influence on brainstem functions, which would secondarily translate into effects on the spinal cord interneurons that are linked to muscular reflexes; hence, the mitigating action on muscular spasm. This understanding has recently been modified by others, who find an inhibitory effect of cyclobenzaprine on mono- and polysynaptic reflex potentials caused by inhibition of the descending serotonergic pathways via the 5-HT2 receptors in the spinal cord  [40] . Whereas this and the preceding elegant studies give credibility and understanding to the muscle relaxation phenomena, none of the studies clearly explain the effect of cyclo­ benzaprine on higher orders of the CNS to the extent that this drug gives rise to sedation and other central neuropsychiatric manifestations, perhaps outside of anticholinergic effects. Such an understanding may very well be useful in furthering the role of this drug in clinical therapeutics. Pain syndromes Low back pain

Low back pain is a common medical problem. In one ambulatory care survey of adults, which spanned a 5-year period, low back pain was the fifth most common presenting medical complaint and was an issue in 2.8% of all office visits [41] The majority of such complaints are labeled as ‘nonspecific’, in contrast to more definitive causes of low back pain. Among patients with low back pain, approximately 20–50% will be prescribed a muscle relaxant of some type, often in combination with an anti-inflammatory agent  [42–44] . Generalists are more likely to prescribe muscle relaxants than are specialty physicians [41] . In one study, cyclobenzaprine comprised nearly a third of the muscle relaxant prescriptions [42] . The elderly were less likely to be prescribed these drugs. The use of muscle relaxants in the setting of general low back pain conditions is of variable benefit [4,43,44] . Furthermore, it is generally held that there is no class of muscle relaxant that is more beneficial than another [45,46] . Studies that have examined the effect of muscle relaxants, including those for cyclobenzaprine specifically, have been fraught with several difficulties: • Low back pain has several causations [29] • Only a proportion of patients with low back pain will suffer muscular spasms • Muscle relaxants as a group are heterogeneous Expert Rev. Clin. Pharmacol. 2(3), (2009)

Cyclobenzaprine: a new look at an old pharmacological agent

The ability of cyclobenzaprine to cause drowsiness during daytime-use ensures that the agent is distinguishable from placebo. Side effects of cyclobenzaprine may prompt alternate-use patterns than are trialed in research studies. Variable dosing and the use of concomitant medications of other classes also seem to cloud comparisons or cumulative analyses. Therefore, it would be anti­cipated that more strict definitions of lower back pain with manifest muscle spasms would be better suited for analysis. Cyclobenzaprine has been directly compared with placebo  [20,29,47–52] . In a dose-ranging study, cyclobenzaprine was no better than placebo when administered as 2.5 mg three-times a day for pooled neck and back pain with spasm, but doses of 5 and 10 mg three-times a day were superior to placebo [20] In other studies, 10 mg three-times a day dosing was consistently superior to placebo and improved outcome measures such as pain, muscle tenderness, spasm, range of motion and ability to perform daily activities [47,51–53] . The beneficial effect is established as early as 2–4 days and continues for as long at 10–14 days. Three studies contrast in their assessment of cyclobenzaprine (10 mg three-times daily) versus diazepam for pooled groups of neck and lumbar pain [29,51,52] . Cyclobenzaprine did not fare better or worse than the muscle relaxant carisoprodol for back pain with spasm [54] . In combination with anti-inflammatory agents, the cumulative effect has been variable. In assessing cyclobenzaprine (5 mg twice daily) with diflunisal for acute back pain, combination therapy was superior [48] . In another study, pairing naproxen with cyclobenzaprine (10 mg three-times daily), combination treatment was more beneficial than cyclobenzaprine alone for back pain with spasm [53] . No significant difference was determined in another trial when both low- and high-dose ibuprofen were combined with cyclobenzaprine (5 mg three-times daily) [55] , and in yet another study (mainly combining acute neck and back pain of myofascial origin), which examined the addition of a standard ibuprofen dose [56] . Evidence-based reviews recognize several problems with existing publications and their reported trials [7,45,57,58] . It is generally agreed that muscle relaxants as a whole, and cyclobenzaprine individually, are moderately effective for acute low back pain with spasm but not for chronic back pain conditions. The evidence was judged as ‘fair’ at best. Muscle relaxants are thought to be as good as but not better than nonsteroidal anti-inflammatory agents for activity in acute back pain treatment but there is no apparent superiority between muscle relaxant groups. Cyclobenzaprine is the best studied of the muscle relaxants, despite the few studies, as detailed earlier. Browning et al. provided a meta-analysis for cyclobenzaprine specifically in its role for back pain [57] . The sedative side-effects of cyclobenzaprine have been cited as a consistent problem, albeit minor. All assessments of cyclobenzaprine have incorporated daytime administration and no studies of single-dose night-time use have been published. Neck pain

Six studies have evaluated cyclobenzaprine among patients with neck pain but each of these are clouded by the pooling of data for both neck and back pain [20,29,49–52] . In one study of acute neck www.expert-reviews.com

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spasm, cyclobenzaprine (30 mg/day) was superior to placebo but no subgroup analysis was given for patients with predominant neck pain [49] . In another series, cyclobenzaprine (15–30 mg/day) provided benefit in a group of patients where approximately a third suffered from neck pain [20] . Two studies examined cyclobenzaprine (30 mg/day) in chronic neck pain and compared it with placebo [50,52] . Cyclobenzaprine was superior to placebo in one of the latter assessments, in which spasm was secondary to osteoarthritis changes; however, the data were pooled for neck and back sources [50] . In the other study, nearly a third of patients had neck pain [52] . The study of cyclobenzaprine in the setting of intractable long-term neck and back pain that was associated with spasm and tenderness did not provide details for the proportion of patients with neck disorders [52] . Yet, others found no benefit from adding cyclobenzaprine to ibuprofen in acute myofascial strain that was, predominantly, of neck and back origin [56] . Peloso et al. have concluded in a Cochrane database review that muscle relaxants, as a group, are of limited benefit in subacute and chronic neck disorders, although the data are meager [59] . Meta-analysis of the few studies that include neck pain, as well as another review, have found some benefit for cyclobenzaprine in particular [8,57] . It is tempting to assume that spasm of musculature from the upper spine, including the neck, should be responsive to cyclobenzaprine in the same fashion that this drug appears to benefit acute low back pain associated with spasm and tenderness. However, larger studies are required to be performed. Fibromyalgia

Fibromyalgia is not uncommonly observed in primary care and remains among the most common diagnoses for patients who are assessed by specialty rheumatologists. Historical confusion over diagnosis has diminished; although, in part, the diagnosis frequently relies on exclusion of other illnesses. Fibromyalgia is characterized by diffuse muscle pains, muscle stiffness, fatigue, tenderness over particularly defined foci and sleep disorder. A number of medical and nonmedical treatments have been trialed. Cyclobenzaprine has now been established as a medical treatment for fibromyalgia, although the mechanism of such benefit is not clearly delineated. In one study, cyclobenzaprine was being used by one in every 25 patients [60] . A recent survey illustrates how the popularity of cyclobenzaprine use in fibromyalgia has escalated [61] . A majority of patients (64%) had consumed cyclobenzaprine at some time and the frequency of use at any time ranked only behind acetaminophen, ibuprofen and naproxen. Approximately 19% were using cyclobenzaprine at the time of the survey and 30% were continuing use. Slightly more than half of patients reported found the drug of value. Cyclobenzaprine was among the top four categories of pharmaceutical-agent use and among the top seven medicines deemed most helpful. Cyclobenzaprine has been assessed against placebo in several studies [62–68] . These have been blinded studies with or without crossover. Daily doses have ranged over 10–40 mg/day and some studies have allowed patients to titrate over this range. Cyclobenzaprine is superior to placebo in the short term [62] but 257

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does not appear to have a long-term sustaining benefit. It is generally recognized that placebo control in this context is difficult, given that patients can readily distinguish cyclobenzaprine over placebo. In a small study of 12 patients, cyclobenzaprine improved sleep and decreased fatigue, but the study did not determine a difference for pain, tender points or mood [64] . In another small study, a significant improvement in sleep was evident but not in pain sensation [65] . A larger study found no change in morning stiffness but found the drug to be associated with improvements for pain, sleep, tender points and muscle tightness [67] . Both patient and physician assessments have identified some benefit of cyclobenzaprine over placebo [66] ; however, the potential benefit of placebo must also be recognized [68] . In a dose-ranging study, 10 mg/night was inferior to 10 mg three-times a day; however, the larger dose created more side effects [69] . The addition of a night-time anti-inflammatory agent, ibuprofen 600 mg, did not provide incremental benefit [70] . Cyclobenzaprine proved equally efficacious to low-dose amitriptyline in the short term [62] . In a randomized controlled trial, cognitive behavioral therapy was of greater benefit than cyclobenzaprine 10 mg/day [63] . Moldofsky’s review concluded that cyclobenzaprine improves the sleep disturbance of fibromyalgia [71] . A contemporary metaanalysis of cyclobenzaprine and placebo found that the drug gave rise to a threefold improvement overall, a modest sleep improvement and decreased pain but no overall benefit for fatigue or tender points [72] . The latter study calculated the need for four or five patients to be treated in order to benefit one. Other pain issues

Cyclobenzaprine (10 mg/night) was compared to clonazepam (0.5  mg/night) and placebo for myofascial joint pain, which included temporomandibular disorders [73] . Cyclobenzaprine was superior to each alternative for decreasing jaw pain on awakening. In a review of post-stroke pain management, it was noted that muscle relaxants had been used in approximately 1% of patients  [74] . Of the four muscle relaxants cited, cyclobenzaprine was by far the most common. No controlled studies in this area are available. The side effect of sedation must be carefully considered in this category of patient. A review of chronic noncancer pain management considered short term use of cyclobenzaprine as beneficial but, again, no critical studies outside of the aforementioned have been published [75] . Some benefit for cyclobenzaprine (30–60 mg/day) over placebo in the treatment of chronic tension headache was observed in a double-blind, crossover trial among 20 patients [76] . Sleep

No well-designed studies have assessed cyclobenzaprine solely as a medication for insomnia. A beneficial effect of cyclobenzaprine on sleep disorders of fibromyalgia patients is perhaps the best studied [64,71] . Reynolds et al., in particular, have meticulously examined a variety of sleep measurements for a small sample of fibromyalgia patients [64] and found a significant benefit for total sleep time in comparison to placebo. Among patients with jaw pain, cyclobenzaprine failed to improve on patients’ 258

subjective reporting of sleep quality, in comparison to clonazepam or placebo [73] . Some patients in the latter study detailed having experienced nightmares as a side effect of the drug. Side effects General

In general, patients receiving cyclobenzaprine have twice the incidence of side effects compared with placebo, if one or more adverse events are reported [49] . The most common side effects relate to the drug’s sedative tendencies and these have been variably termed drowsiness, fatigue, asthenia, somnolence, dizziness, lightheadedness and sedation [8,49,51,55,67] . Frequencies of the latter from various studies have ranged from 0–84%; however, they have been documented significantly more often when compared with placebo. Others have reported nausea. Anticholinergic effects, as previously detailed, also occur. Among the latter, dry mouth for example, has been reported from 0 to 14%. These side effects increase proportionately with higher or multiple daily dosages. Similar effects have been observed in the initial clinical research phases, subsequent comparative clinical trials and postmarketing surveillance [77] . In one large cohort of patients from randomized trials, no major adverse reaction was reported [55] . A general review cites a 0.2–1.4% frequency of adverse effects, to include altered taste, tachycardia, confusion, disorientation and hallucinations  [5] . The occurrence of anticholinergic side effects has given rise to cautionary use and/or avoidance among those at risk of urinary retention and glaucoma, such as the elderly. Interactions with other drugs are uncommonly reported; although, enhancement of the sedative effect with other CNSacting agents occurs. An increased risk of seizures with concomitant tramadol was suggested [74] . A serotonin syndrome has been also been experienced [78] when cyclobenzaprine was coadministered with proserotoninergic medication, such as monoamine oxidase inhibitors, selective serotonin-reuptake inhibitors and duloxetine. This syndrome is putatively caused by an excess of serotonin receptor activation on both central and peripheral system levels. Common manifestations of the latter can include agitation, tachycardia, irregularities in blood pressure (often labile), profuse sweating, hyperthermia, pupillary dilatation, diarrhea, limb tremor and/or hyper-reflexia, clonus, and muscular rigidity. The intensity of such manifestations is variable but can, potentially, be deadly. It has, therefore, been proposed that cyclo­benzaprine should not be used within 14 days of monoamine oxidase inhibitors [10,74] . A neuroleptic malignant syndrome including fever, leuko­cytosis, increased creatine phosphokinase, muscle rigidity and delirium was reported for a young man [79] ; although, it was unclear if the episode was idiosyncratic or a possible overdose. Acute psychiatric decompensation has been reported [27,80–83] . The events have been variably termed psychosis, delirium, hallucinations and mania. One episode occurred in a previously well individual, others among elderly patients and as exacerbations of psychosis in known bipolar patients. Resolution was obtained soon after the drug was discontinued. A sole case of cyclo­benzaprine-associated hypoglycemia was reported [84] . Expert Rev. Clin. Pharmacol. 2(3), (2009)

Cyclobenzaprine: a new look at an old pharmacological agent

Low-dose cyclobenzaprine has minimal effects on the elderly [85] ; however, typical clinical doses may cause confusion and other cognitive disturbances among these patients [80,82] . However, poly­ pharmacy may complicate the apparent role of cyclo­benzaprine in acute toxicities [86] and this is more likely to be pertinent to elderly patients. Beers has categorized cyclo­benzaprine as an agent that is inappropriate for geriatric use [87] . Overdose

Cyclobenzaprine has been deemed less toxic than similarly structured tricyclic agents. Nonetheless, experience with overdoses has been considerable [88–94] . Among muscle relaxants, cyclobenzaprine has been cited the most often in the context of overdose and poison control when single-agent ingestion is enumerated; however, a large proportion of the drug’s citations in overdose use are co-ingestions [94] . Fatal overdoses have been published, in which post-mortem blood levels have exceeded 0.8 mg/l. One review of five poison control centers, however, found no deaths in the context of over 400 pure cyclobenzaprine ingestions [88] . In the latter review, doses ranged from 5–1000 mg (mean: 133 mg). Clinical toxicity, when apparent, occurred after approximately 1.5 h and as late as 4 h after infusion. The most common effects included lethargy, agitation, tachycardia and variable influences on blood pressure. These were often believed to be due to anticholinergic mechanisms. Few cardiac arrhythmias were detailed and none of the patients developed seizures. QT interval prolongation has been observed [74] and, therefore, caution has been raised for cyclobenzaprine use among patients with arrhythmias, conduction defects and recent myocardial infarction. Laboratory changes indicative of rhabdomyolysis were discussed in two reports [89,93] . In general, the severity of intoxication is much less than expected from other tricyclic agents that may create major cardiotoxicities. Adults ingesting less than 100 mg generally do not have serious side effects. Thus, the latter group may receive largely supportive therapy with or without gastric decontamination. For those with ingestions over 100 mg, supportive strategies have included gastric emptying, mechanical ventilation, fluids, sedation, urinary catheterization and vasopressors. The drug’s anticholinergic effects may directly delay gastric emptying and, hence, recovery of ingested tablets from gastric lavage is possible. Physostigmine has been utilized in severe circumstances to counter the anticholinergic phenomena [91,92] ; although, caution in its use has been advocated. Abuse potential

As one might anticipate, a mood-altering medication might be seen by some as an opportunity for abuse [4] . In this light, cyclobenzaprine has been referred to as ‘cyclone’ or ‘mellow yellow’, and recreational doses of 20–80 mg lead to considerable drowsiness and relaxation. Combinations with alcohol [95,96] and multidrug use [16] are detailed. The latter has been associated with patient demise. Despite the drug’s availability, it has not made major inroads in circles of illicit drug use and trade. www.expert-reviews.com

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Conclusion

Cyclobenzaprine is a tricyclic pharmacological agent, which has been available for several decades and enjoys considerable use as a muscle relaxant. It is among the most commonly used generic drugs and is among the most widely studied agents classified as muscle relaxants. The agent, as originally formulated, is often prescribed in multidose fashion; although, clinically, it is not uncommonly administered at night time. A sustained-release formulation is becoming available. Dosages of 5–20 mg are typically administered. The drug has modest bioavailability and it is subject to modification in the liver after absorption. A variety of metabolites occur but only a minor proportion are found as a conjugate in the urine. This agent gives rise to anticholinergic side effects and is also commonly associated with sedative properties. Whereas it was believed that the skeletal muscle-relaxing effects were thought to be mediated by noradrenergic coeruleus–spinal or reticulospinal pathways, others have found an inhibitory effect on mono- and poly-synaptic reflex potentials, caused by inhibition of descending serotonergic pathways via 5-HT2 receptors in the spinal cord. Cyclobenzaprine is moderately active in acute low back pain with spasm but not in chronic back pain. It is thought to be as good as but not better than NSAIDs in the latter context, and it is, therefore, clinically not uncommonly used in combination. The results of these studies have been extended to spasm of and pain from musculature of the upper spine. In general, such studies lack many of the design stringencies that would be required at present. Cyclobenzaprine has now been established as a medical treatment for fibro­myalgia, and is superior to placebo in the short but not long term. Furthermore, it has a beneficial effect on sleep disorders of fibromyalgia. The side effects of cyclobenzaprine use are usually sedative, but care should be exercised in using the drug for the elderly, pediatrics, patients currently consuming proserotoninergic medication, other psychiatric patients and patients who are at risk of drug abuse. Overdoses of the drug should be largely treated by supportive measures with or without gastric decontamination and aggressive measures are more likely to be required when the total amount of drug consumed exceeds 100 mg. Despite common use as a skeletal muscle relaxant, cyclo­benzaprine is relatively understudied and may yet enjoy a renaissance in both clinical and basic research, as well as clinical use. Expert commentary

Cyclobenzaprine has attracted medical use for several decades, albeit mainly for illnesses in which muscle relaxation has been desirable. The CNS acting effects are numerous, however, and there is potential for this drug to be a sole agent for, or adjunct in, the management of other illnesses, especially in the neuropsychiatric spectrum. The drug has a relatively safe profile and cautious consideration should be made for expanding its use after well-designed clinical trials. A drug with such diverse activity could, seemingly, be of value in contexts other than those detailed earlier. Many of the studies that were applied to the more common usages are unlikely to 259

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pass the scrutiny of contemporary investigators and state-of-theart methodology. It would be prudent, therefore, to ensure that well-conducted clinical science is applied to any further study. The short-term use of cyclobenzaprine is relatively safe and well-documented. The effects of long-term use, however, require further observation. Single, night-time, pulsed and rotating dosing should be considered. Combination treatment with other medication, whether for additive or synergistic effects, deserves attention, as well as the potential for drug interactions or antagonisms. Whereas much study has been directed to the muscle relaxant properties of cyclobenzaprine, it is apparent that there are a variety of potential neuropsychiatric effects. Although cyclobenzaprine was initially assessed and, thereafter, disregarded for its effect on depression, a potential role in psychiatry treatment could reemerge, albeit with caution given the proserotoninergic capabilities. For example, there may be merit in assessing the therapeutic potential for short-term travel phobia or chronic anxiety. It is evident that patient profiles for those who were enrolled in former studies of neck and back pain were diverse. Further studies of muscle-associated pain syndromes could more narrowly define patient inclusion, for example, post-motor vehicle accident whiplash of the neck, nontraumatic torticollis and post-fracture muscle pain. The homogeneity of clinical illnesses under study adds to the precision of combining a drug for a specific effect or pathology. An open mind should also be maintained to possibly apply cyclobenzaprine in the treatment for such diverse maladies as insomnia, hiccups, irritable bowel, nocturnal leg cramps, muscle fasciculations, various movement disorders and intractable pain syndromes.

Five-year view

Cyclobenzaprine will continue to be used consistently over the next 5 years due to its relative safety and reasonable efficacy in a diverse array of medical illnesses. Time-release formulations will be increasingly studied and clinically utilized. Further assessments of cyclobenzaprine use would be prudent in times of healthcarerelated economic constraints. Given the availability of cyclobenzaprine in generic form, it is less likely that industry-funded studies of alternate use will be forthcoming in great measure. The potential cost savings for using such a low-cost drug will, more likely, be attractive to public healthcare providers and such a source for funding may force the need for well-designed scientific studies that provide strong evidence-based support. There is still plenty of opportunity for cyclobenzaprine to be assessed and, potentially, used in a greater spectrum of medical illnesses than is currently realized. Alongside such greater clinical use, basic science research merits resurgence. The vast majority of existing pharmacological research delves into the putative mechanism of action in muscle relaxation. However, there is still much to realize how cyclobenzaprine achieves CNS activity, aside from anti­cholinergic properties. Furthermore, long-term use of this drug requires examination. Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Cyclobenzaprine continues to be prescribed widely as a skeletal muscle relaxant. • There is moderately consistent evidence to support the use of cyclobenzaprine in acute spasmodic neck and back muscular pain. • Cyclobenzaprine can be a useful adjunct for short-term treatment of fibromyalgia. • Muscle-relaxation effects are believed to be caused by inhibition of descending serotoninergic pathways in the spinal column. • Cyclobenzaprine is a well-tolerated pharmacological agent, whose side effects are mainly sedative in nature. • Cyclobenzaprine has anticholinergic properties. • Most cyclobenzaprine overdoses are easily managed.  • Due to its CNS effects, cyclobenzaprine is a potential agent for abuse. Markets. Fraser Institute Digital Publication. The Fraser Institute, Vancouver, BC, Canada (2008).

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Hucker HB, Balletto AJ, Arison BH, Zacchei AG. Metabolism of cyclobenzaprine in the dog. Drug Metab. Disp. 6, 184–192 (1978). Pachecka J, Salmona M, Cantoni L et al. Activity of liver microsomal monooxygenases on some epoxide-forming tricyclic drugs. I. Kinetics in vitro. Xenobiotica 6, 593–598 (1976). Obach RS, Huynh P, Allen MC, Beedham C. Human liver aldehyde oxidase: inhibition by 239 drugs. J. Clin. Pharmacol. 44, 7–19 (2004).

Till AE, Constanzer ML, Demetriades J, Irvin JD, Lee RB. Evidence for route dependent biotransformation of cyclobenzaprine hydrochloride. Biopharm. Drug Disp. 3, 19–28 (1982).

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Lofland JH, Szarlej D, Buttaro T, Shermock S, Jalali S. Cyclobenzaprine hydrochloride. Clin. J. Pain 17, 103–104 (2001).

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Hucker HB, Stauffer SC, Albert KS, Lei BW. Plasma levels and bioavailability of cyclobenzaprine in human subjects. J. Clin. Pharmacol. 17, 719–727 (1977).

O’Neil BA, Knudson GA, Bhaskara SM. First episode psychosis following cyclobenzaprine use. Can. J. Psychiatry 45, 763–764 (2000).

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Levine B, Jones R, Smith ML, Gudewicz TM, Peterson B. A multiple drug intoxication involving cyclobenzaprine and ibuprofen. Am. J. Forensic Med. Pathol. 14, 246–248 (1993).

Hughes MJ, Lemons S, Barnes C. Cyclobenzaprine: some pharmacological cardiac actions. Life Sci. 23, 2779–2786 (1978).

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Hawes EM. N + -glucuronidation, a common pathway in human metabolism of drugs with a tertiary amine group. Drug Metab. Disp. 26, 830–837 (1998).

Nibbelink DW, Strickland SC, McLean LF, Gould AL. Cyclobenzaprine, diazepam and placebo in the treatment of skeletal muscle spasm of local origin. Clin. Ther. 1, 409–424 (1978).

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Hucker HB, Stauffer SC, Balletto AJ, White SD, Zacchei AG, Arison BH. Physiological disposition and metabolism of cyclobenzaprine in the rat, dog, rhesus monkey, and man. Drug Metab. Disp. 6, 659–672 (1978).

30

Barnes CD. Effects of cyclobenzaprine on brainstem motor systems. Neuropharmacology 15, 643–652 (1976).

31

Barnes CD, Adams WL. Effects of cyclobenzaprine on interneurones of the spinal cord. Neuropharmacology 17, 445–450 (1978).

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19

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Darwish M, Hellriegel ET, Xie F. Single-dose pharmacokinetics of once-daily cyclobenzaprine extended release 30 mg versus cyclobenzaprine immediate release 10 mg three times daily in healthy young adults: a randomized, open-label, two-period crossover, single-centre study. Clin. Drug Invest. 28, 793–801 (2008). Borenstein DG, Korn S. Efficacy of a low-dose regimen of cyclobenzaprine hydrochloride in acute skeletal muscle spasm: results of two placebo-controlled trials. Clin. Ther. 25, 1056–1073 (2003).

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Esplin B, Capek R. Effects on cyclobenzaprine on spinal synaptic transmission. Neuropharmacology 18, 559–564 (1979).

33

Share NN. Cyclobenzaprine: studies on its site of muscle relaxant action in the cat. Neuropharmacology 19, 757–764 (1980).

34

Share NN. Cyclobenzaprine: effect on segmental monosynaptic and tonic vibration reflexes in the cat. Neuropharmacology 17, 721–727 (1978).

Review

35

Share NN, McFarlane CS. Cyclobenzaprine: a novel centrally acting skeletal muscle relaxant. Neuropharmacology 14, 675–684 (1975).

36

Share NN. Cyclobenzaprine: effect on tonic vibration reflexes in local tetanus cat preparations. Neuropharmacology 23, 947–953 (1984).

37

Barnes CD, Fung SJ, Gintautas J. Brainstem noradrenergic system depression by cyclobenzaprine. Neuropharmacology 19, 221–224 (1980).

38

Commissiong JW, Karoum F, Reiffenstein RJ, Neff NH. Cyclobenzaprine: a possible mechanism of action for its muscle relaxant effect. Can. J. Physiol. Pharmacol. 59, 37–44 (1981).

39

Lang IM, Barnes CD. Cyclobenzaprine effects on locus coeruleus cells in tissue slice. Neuropharmacology 22, 249–252 (1983).

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Honda M, Nishida T, Ono H. Tricyclic analogs cyclobenzaprine, amitriptyline and cyproheptadine inhibit the spinal reflex transmission through 5-HT2 receptors. Eur. J. Pharmacol. 458, 91–99 (2003).

•• Elucidates the pharmacological mechanism of action, which, for many years, was believed to be more direct on the locus coeruleus. 41

Hart LG, Deyo RA, Cherkin DC. Physician office visits for low back pain: frequency, clinical evaluation, and treatment patterns from a U.S. national survey. Spine 20, 11–19 (1995).

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Luo X, Pietrobon R, Curtis LH, Hey LA. Prescription of nonsteroidal antiinflammatory drugs and muscle relaxants for back pain in the United States. Spine 29, E531–E537 (2004).

•

Provides a clinical context for common uses of muscle relaxants and similar agents.

43

Cherkin DC, Wheeler KJ, Barlow W, Deyo RA. Medication use for low back pain in primary care. Spine 23, 607–614 (1998).

44

Bernstein E, Carey TS, Garrett JM. The use of muscle relaxant medications in acute low back pain. Spine 29, 1346–1351 (2004).

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Chou R, Hoyt-Huffman L. Medications for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Ann. Intern. Med. 147, 505–514 (2007).

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Evidence-based review.

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Carragee EJ. Persistent low back pain. N. Engl. J. Med. 352, 1891–1898 (2005).

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Baratta RR. A double-blind study of cyclobenzaprine and placebo in the treatment of acute musculoskeletal conditions of the low back. Curr. Ther. Res. 32, 646–652 (1982).

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Basmajian JV. Acute back pain and spasm: a controlled multicenter trial of combined analgesic and antispasm agents. Spine 14, 438–439 (1989).

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Steingard PM, Shildberg WL, Peterson KD. Multiclinic study of a muscle relaxant for treatment of acute musculoskeletal disorders. Osteopath. Ann. 8, 294–302 (1980).

50

Bercel NA. Cyclobenzaprine in the treatment of skeletal muscle spasm in osteoarthritis of the cervical and lumbar spine. Curr. Ther. Res. 22, 462–468 (1977).

51

Brown BR Jr. Cyclobenzaprine in intractable pain syndromes with muscle spasm. JAMA 240, 1151–1152 (1978).

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Basmajian JV. Cyclobenzaprine hydrochloride effect on skeletal muscle spasm in the lumbar region and neck: two double-blind controlled clinical and laboratory studies. Arch. Phys. Med. Rehabil. 59, 58–63 (1978).

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Borenstein DG, Lacks S, Wiesel SW. Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm. Clin. Ther. 12, 125–131 (1990).

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Rollings HE, Glassman JM, Soyka JP. Management of acute musculoskeletal conditions – thoracolumbar strain or sprain: a double-blind evaluation comparing the efficacy and safety of carisoprodol with cyclobenzaprine hydrochloride. Curr. Ther. Res. 34, 917–928 (1983). Childers MK, Borenstein D, Brown RL et al. Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial. Curr. Med. Res. 21, 1485–1493 (2005). Turturro MA, Frater CR, D’Amico FJ. Cyclobenzaprine with ibuprofen versus ibuprofen alone in acute myofascial strain: a randomized, double-blind clinical trial. Ann. Emerg. Med. 41, 818–826 (2003). Browning R, Jackson JL, O’Malley PG. Cyclobenzaprine and back pain: a meta-analysis. Arch. Intern. Med. 161, 1613–1620 (2001). Systematic review of cyclobenzaprine in its main area of usage.

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van Tulder MW, Touray T, Furlan AD, Solway S, Bouter LM. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane Collaboration. Spine 28, 1978–1992 (2003).

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Santandrea S, Montrone F, Sarzi-Puttini P, Boccassini L, Caruso I. A double-blind crossover study of two cyclobenzaprine regimens in primary fibromyalgia syndrome. J. Int. Med. Res. 21, 74–80 (1993).

•• A meticulous and timely review of muscle relaxants in their role for low back pain.

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Fossaluzza V, De Vita S. Combined therapy with cyclobenzaprine and ibuprofen in primary fibromyalgia syndrome. Int. J. Clin. Pharm. Res. 12, 99–102 (1992).

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Moldofsky H. Management of sleep disorders in fibromyalgia. Rheum. Dis. Clin. N. Am. 28, 353–365 (2002).

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Tofferi JK, Jackson JL, O’Malley PG. Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis Rheum. 51, 9–13 (2004).

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Peloso P, Gross A, Haines T et al. Medicinal and injection therapies for mechanical neck disorders (review). Cochrane Database Syst. Rev. 18(3), CD000319 (2007).

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Rico-Villademoros F, Hidalgo J, Dominguez I, Garcia-Leiva JM, Calandre EP. Atypical antipsychotics in the treatment of fibromyalgia: a case series with olanzapine. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 161–164 (2005).

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Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people in fibromyalgia. BMC Musculoskelet. Disord. 8, 27 (2007).

•• Excellent review article on the use of cyclobenzaprine in fibromyalgia, which carefully considers evidencebased medicine.

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Herman CR, Schiffman EL, Look JO. The effectiveness of adding pharmacologic treatment with clonazepam or cyclobenzaprine to patient education and self-care for the treatment of jaw pain upon awakening: a randomized clinical trial. J. Orofac. Pain 16, 64–79 (2002).

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Zorowitz RD, Smout RJ, Gassaway JA, Horn SD; Post-Stroke Rehabilitation Outcomes Project. Usage of pain medications during stroke rehabilitation: (PROSP). Top. Stroke Rehabil. 12, 37–49 (2005).

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Merskey H. Pharmacological approaches other than opioids in chronic non-cancer pain management. Acta Anaesthesiol. Scand. 41, 187–190 (1997).

76

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Nibbelink DW, Strickland SC. Cyclobenzaprine (Flexeril®) postmarketing surveillance program: preliminary report. Curr. Ther. Res. 25, 564–571 (1979).

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Keegan MT, Brown DR, Rabinstein AA. Serotonin syndrome from the interaction of cyclobenzaprine with other serotoninergic drugs. Anesth. Analg. 103, 1466–1468 (2006).

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Theoharides T, Scott HR, Weckstein D. Neuroleptic malignant-like syndrome due to cyclobenzaprine? J. Clin. Psychopharmacol. 15, 79–81 (1995).

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Douglass MA, Levine DP. Hallucinations in an elderly patient taking recommended doses of cyclobenzaprine. Arch. Intern. Med. 160, 1373 (2000).

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Reynolds WJ, Moldofsky H, Saskin P, Lue FA. The effects of cyclobenzaprine on sleep physiology and symptoms in patients with fibromyalgia. J. Rheumatol. 18, 452–454 (1991). Hamaty D, Valentine JL, Howard R, Howard CW, Wakefield V, Patten MS. The plasma endorphin, prostaglandin and catecholamine profile of patients with fibrositis treated with cyclobenzaprine and placebo: a 5-month study. J. Rheumatol. 16(Suppl. 19), 164–168 (1989). Quimby LG, Gratwick GM, Whitney CD, Block SR. A randomized trial of cyclobenzaprine for the treatment of fibromyalgia. J. Rheumatol. 16(Suppl. 19), 140–143 (1989). Bennett RM, Gatter RA, Campbell SM, Andrews RP, Clark SR, Scarola JA. A comparison of cyclobenzaprine and placebo in the management of fibrositis. Arthritis Rheum. 31, 1535–1542 (1988). Campbell SM, Gatter RA, Clark S, Bennett RM. A double blind study of cyclobenzaprine versus placebo in patients with fibrositis. Arthritis Rheum. 27, S76 (1984).

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Cyclobenzaprine: a new look at an old pharmacological agent

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Beeber AR, Manring JM. Psychosis following cyclobenzaprine use. J. Clin. Psychiatry 44, 151–152 (1983).

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Engel PA, Chapron D. Cyclobenzaprineinduced delirium in two octogenarians. J. Clin. Psychiatry 54, 39 (1993).

83

Harsch HH. Mania in two patients following cyclobenzaprine. Psychosomatics 25, 791–793 (1984).

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Spiller HA, Winter ML, Mann KV, Borys DJ, Muir S, Krenzelok EP. Five-year multicenter retrospective review of cyclobenzaprine toxicity. J. Emerg. Med. 13, 781–785 (1995).

•

A general view of cyclobenzaprine toxicities and the issues that they create, as well as an appreciation of the relative safety profile of this drug.

Alim M, Edelson GW. Syncope in a young woman with chronic back pain. Hosp. Pract. 28, 80–82 (1993).

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Chabria SB. Rhabdomyolysis: a manifestation of cyclobenzaprine toxicity. J. Occup. Med. Toxicol. 1, 16 (2006).

Lines C, Traub M, Raskin S, Mant T, Reines S. Lack of sedative and cognitive effects of diphenhydramine and cyclobenzaprine in elderly volunteers. J. Psychopharmacol. 11, 325–329 (1997).

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Spiller HA, Cutino L. Fatal cyclobenzaprine overdose with postmortem values. J. Forensic Sci. 48, 883–884 (2003).

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92

Stephen JM, Ghezzi KT, Bailey K, Shesser R. Post-triathalon delirium. J. Emerg. Med. 9, 265–269 (1991).

93

O’Riordan W, Gillette P, Calderon J, Stennes RL. Overdose of cyclobenzaprine, the tricyclic muscle relaxant. Ann. Emerg. Med. 15, 592–593 (1986).

94

Lebby TI, Dugger K. Skeletal muscle relaxant ingestion. Vet. Hum. Toxicol. 32, 133–135 (1990).

Rosenlicht NZ, Riley-Lazo KP. Interactions of cyclobenzaprine and tricyclic antidepressants. J. Clin. Psychiatry 66, 134–135 (2005).

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Beers MH. Explicit criteria for determining potentially inappropriate medication use by the elderly: an update. Arch. Intern. Med. 157, 1531–1536 (1997).

•

A must-read for those who are interested in defining appropriate therapies for geriatric populations.

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Review

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Messiha FS, Barnes CD. Cyclobenzaprine and ethanol interaction. Pharmacol. Biochem. Behav. 10, 947–949 (1979).

96

Winek CL Jr, Wahba WW, Winek CL. Drowning due to cyclobenzaprine and ethanol. Forensic Sci. Int. 100, 105–108 (1999).

Affiliation •

Nevio Cimolai, MD, FRCP(C) Department of Pathology and Laboratory Medicine, Faculty of Medicine, The University of British Columbia, Canada and Department of Pathology and Laboratory Medicine, Children’s and Women’s Centre of British Columbia, Vancouver, BC V6H 3V4, Canada Tel.: +1 604 271 9321 Fax: +1 604 271 9321 [email protected]

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