Understanding the Fibromyalgia Syndrome

Srinivas G. Rao, MD, PhD; Judith F. Gendreau, MD; Jay D. Kranzler, MD, PhD

Disclosures

Psychopharmacol Bull. 2008;40(4):24-56. 

In This Article

Clinical Pharmacology of FMS

At the time the preceding review was written, the vast majority of published results from randomized, controlled studies in FMS examined the use of tricyclic antidepressants; other therapeutic approaches generally had relatively limited data to support their usage.[38] Further, a large percentage of the existing clinical data was derived from relatively small studies, often with high dropout and placebo response rates.[177,178] These trials tended to be of short duration with very limited information regarding the long-term efficacy of any of the agents. As described below, recent trials have addressed a number of these criticisms.

Other issues still remain, however.While the 1990 ACR criteria for the classification of FMS have helped standardize the identification of patients appropriate for entry into clinical trials,[3,179] the group remains extremely diverse and heterogeneous. The issue of co-morbid depression and its impact on patients' responses to therapeutic interventions is also critical in the design of FMS trials, as will be expanded upon below. Standard practice has been to exclude patients with "severe" psychiatric illness from clinical trials, by incorporating cut-off criteria when using standard psychometric instruments such as the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), or the Beck Depression Inventory (BDI) as prescreening tools.[180,181,182,183,184] However, a great deal more information is required before the complex inter-relationships between depression, pain, and other symptoms of FMS can be ascertained.

A wide variety of approaches—both pharmacological and nonpharmacological— have been applied, with varying degrees of success, towards the treatment of the symptoms of FMS. At the present time, the management of fibromyalgia patients involves a complex interplay between the pharmacological management of pain and associated symptoms and the use of non-pharmacological modalities. As the elimination of all FMS symptoms is not currently possible (ie, a cure), the philosophy of management is symptom palliation and function a l restoration. The presentation of fibromyalgia symptomatology is highly variable and each patient must have an individualized evaluation before deciding upon an initial treatment plan.[185] Regular follow-up and modification of the initial management strategy is usually required, depending upon the patient's response.

Several recent publications have reviewed the current state of FMS therapy; the data from randomized, double-blind, placebo- or activecontrolled trials are summarized in Table 1 .[178,186,187,188,189,190,191,192] In this section, we have chosen to briefly review a number of the many agents that have been employed to treat FMS. A drug was included in the summary if it met one or more of the following criteria:

  1. A large quantity of clinical data in FMS patients exists, eg TCAs, SSRIs, DRIs, pregabalin, and 5HT3 receptor antagonists.

  2. The clinical investigation of the drug has been based on solid preclinical scientific data, eg, NK1 antagonists, NMDA antagonists, and GH.

  3. The drugs have other psychiatric indications, eg, "mood stabilizers" or anti-epileptic drugs (AEDs), atypical anti-depressants, anxiolytics, hypnotics, and α2 adrenergic agonists, acting as antispasticity agents, such as clonidine and tizanidine.

Some of these drugs can be supported as primary therapy.Others may have an adjuvant role addressing symptoms other than pain and important in the overall management of these patients.

The majority of FMS clinical trials have involved antidepressants of one class or another, as is evident from Table 1 . Trials studying the oldest class of agents, tricyclic antidepressants are abundant, though most recent studies have focused on selective serotonin reuptake inhibitors and "atypical antidepressants"—a class that includes dual reuptake inhibitors and monoamine oxidase inhibitors. Despite the multiplicity of antidepressant classes, practically all of the agents currently in clinical use either directly or indirectly increase neurotransmission mediated by the monoamine neurotransmitters, particularly serotonin (5-HT) and/or norepinephrine (NE; also called noradrenaline).[193] These activities are thought to underlie the antidepressant activity of these compounds, though the exact mechanism by which this occurs is unknown. These pharmacological activities also appear to be an important mechanism by which antidepressant compounds effect centrally-mediated analgesia.[193]

Excepting TCAs, current classification schemes have tended to segregate agents based on their in vitro effects upon 5-HT and NE re-uptake activity. As shown in Table 2 , specific agents within a given class vary significantly in terms of their relative actions on the reuptake of these two monoamines or upon binding to their respective transporters.[194,195,196,197,198,199] Note, however, that the effects of these agents in vivo may differ significantly from those observed in vitro. For example, despite its low affinity for the NE transporter, venlafaxine has been shown to have in vivo effects consistent with NE reuptake blockade, particularly at higher doses.[200,201,202] Conversely, despite the marked difference in relative affinities for the NE and 5-HT transporters that paroxetine displays in vitro, recent data suggests that this agent may possess dual reuptake inhibitory activity in vivo at clinically relevant doses.[203]

Tricyclic Antidepressants (TCAs). TCAs—particularly amitriptyline and doxepin—are widely employed in the treatment of FMS and other chronic pain conditions. (Cyclobenzaprine is also widely used in the treatment of FMS and is structurally very similar to amitriptyline. However, cyclobenzaprine is typically classified as a muscle relaxant rather than an antidepressant and will be discussed below).[186,187,188] Multiple studies support the use of TCAs for the treatment of FMS. Members of this class have frequently been used as the positive controls to which newer agents have been compared .[204,205,206,207,208] The results from TCA trials in FMS have been compiled and analyzed in two meta-analyses by Arnold et al.[176] and O'Malley et al.[188] In essence, the authors both conclude that TCAs provide "moderate" improvement in FMS, with the greatest impact on measurements of sleep, overall well-being, and pain severity. More specifically, Arnold et al. report significant clinical response to TCAs was observed in 25-37% of patients, whereas O'Malley et al. report patients receiving TCAs "four times as likely" to report overall improvement (compared to placebo) and experience moderate reductions in individual symptoms.

Pharmacologically, most TCAs block the reuptake of both 5-HT and/or NE, with varying degrees of relative activities ( Table 2 ). However, amitriptyline, nortriptyline, and dexopin all preferentially block the reuptake of NE with greater potency than that of 5-HT, with selectivity ratios (relative ability to block NE versus 5-HT uptake) ranging from 1.1 for amitriptyline to 168 for nortriptyline. Amitrip tyline (with a half-life of 12-36 hours) is metabolized primarily to nortriptyline (with a half-life of 22-88 hours),[169] further adding to the NE bias of amitriptyline especially at the lower dosages which have been historically used to treat chronic pain. The general efficacy of TCAs in treating the pain of FMS, therefore, can be interpreted to support the primacy of NE agonism for analgesic activity. Beyondinc reasing NE and 5-HT levels, TCAs have other important pharmacologic properties, including dopamine reuptake inhibition, NMDA antagonism, and ion-channel blocking activity.[209,210,211,212,213,214,215,216] Therefore, there is overlap between the mechanisms of action of the tricyclics and other agents, such as anti-epileptic agents (ie, ion-channel blockade). TCAs additional anti-cholinergic, anti-histaminergic, and a-adrenergic receptor blockade activities impart a wide assortment of undesirable side effects, which often compromise the tolerability and clinical acceptance of this class.[217]

Somewhat ironically, the data supporting the use of TCAs in treating depressed mood in the context of FMS or other pain states is limited, perhaps as a result of most trials evaluatng sub-antidepressant doses of TCAs.[38,187] In most forms of major depressive disorder, however, the efficacy and remission rates of TCAs are equal or superior to those of other classes of agents, an effect hypothesized to result from their effects on both the serotonergic and noradrenergic systems.[218]

Although the anti-depressant activity of these agents may contribute to the efficiency seen in certain patients, their role as centrally-acting analgesics appears to be more critical. This premise is supported by results from trials of various SSRIs, which, in general, do not appear to be as effective analgesics as TCAs even at anti-depressant doses (see below).

Selective Serotonin Reuptake Inhibitors (SSRIs). SSRIs have revolutionized the field of psychiatry, providing safe and effective treatment of common psychiatric conditions including major depressive disorder, anxiety, and social phobia. Much of their success is attributable to the fact that SSRIs display improved tolerability compared to TCAs, a result of their much higher degree of pharmacological specificity. As implied by their name, SSRIs primarily inhibit the reuptake of 5-HT, and they typically lack the extra-monoaminergic activities which characterize TCAs. The SSRIs fluoxetine, citalopram, sertraline, and paroxetine have each been evaluated in randomized, placebo-controlled trials in FMS.[219,220] The results of these trials have been somewhat inconsistent, leaving some debate regarding the relative efficacy of the SSRIs, especially in comparison to TCAs. Two studies have demonstrated positive efficacy for fluoxetine when compared to either placebo or amitriptyline in treating sleep, pain, fatigue, and depression.[205,219] However, a third study failed to demonstrate any significant improvement in pain, although mild improvements were noted in sleep and depression.[221] Two placebo-controlled trials of citalopram have been performed; the first was convincingly negative, with citalopram failing to demonstrate any improvements in pain, fatigue, sleep, or mood.[222] The second study demonstrated that citalopram significantly improved mood, though other outcome measures did not improve significantly.[223] One study comparing sertraline to amitriptyline demonstrated that the two compounds were equivalent in producing significant improvements in pain, sleep, and fatigue.[224] Finally, a study comparing paroxetine to amitripty line concluded that, while both improved the symptoms of pain, sleep, and depression, amitriptyline had a larger, more robust effect.[220] Further, amitriptyline was beneficial for fatigue whereas paroxetine did not improve this symptom. Taken together, SSRIs appear to be effective in treating certain FMS symptoms, particularly mood. However, their effect sizes on pain, sleep, and fatigue appear to be less robust in comparison to amitriptyline and the dual reupake inhibitors.

These data—particularly those pertaining to citalopram, the most 5-HT-specific of the SSRIs (see Table 2 )—suggest that serotonergic activity alone is not sufficient to effect analgesia in the chronic pain setting. In fact, the SSRIs as a class are, generally, less efficacious than the in chronic pain states, based on the evidence assembled to date,[15,40,90,111,225] although there are some exceptions.[226,227]

Dual-Reuptake Inhibitors (DRIs) Antidepressants. The term "novel" antidepressant covers a great deal of pharmacological variety, including 5-HT/NE dual reuptake inhibitors (DRIs), NE- specific reuptake inhibitors (NRRIs), 5-HT receptor antagonists, and monamine-oxidase (MAO) inhibitors, among others.[217] DRIs are pharmacologically similar to some TCAs in their ability to inhibit the reuptake of both 5-HT and NE, a feature that may improve their analgesic efficacy as reviewed in Rao.[193] Importantly, DRIs differ from TCAs in being gene rally devoid of significant activity at other receptor systems, and this selectivity results in diminished side effects and enhanced tolerability.[193] Venlafaxine is the only DRI currently available within the US and is currently indicated for depression and anxiety. Two open label studies suggest venlafaxine is useful in treating multiple symptoms of FMS.[228,229] However, these results were not replicated by a recent randomized placebo controlled trial, in which patients treated with venlafaxine did not show any significant improvements in pain, fatigue, sleep, or mood compared to those on placebo.[230] These results may be explained by dosing, as the study by Dwight et al.[231] pushed each patient to their maximally tole rated dose or 375 mg/day (mean 167 mg/day ) , while a study by Zijlstra et al.[232] had a single drug arm with a dose of 75 mg/day.Data suggests that venlafaxine is primarily a 5-HT reuptake inhibitor at lower doses (ie,,150 mg), with NE effects apparent on ly at higher doses.[200,201] On the other hand, it should be noted that the open-label trial by Sayar et al.[233] also used a single dose of 75 mg and found it effective against various FMS symptoms.

Milnacipran is a DRI presently available in Japan and parts of Europe for the treatment of depression. This agent is unique among clinically available DRIs in its preferential blockade of NE reuptake over 5-HT ( Table 2 ); additionally, this compound is a low affinity NMDA antagonist. 198 Milnacipran is presently in clinical development for FMS in the US, and the results of a Phase II monotherapy trial were recently announced.[234] Placebo was compared to milnacipran, dosed both once and twice daily (when used as an antidepressant, milnacipran is dosed twice daily). All patients were escalated over a 4-week interval to either the maximum tolerated dose of milnacipran or to a total of 200 mg/day. The total trial duration was 12 weeks, (the primary endpoint was pain) tracked on a near-real-time basis using an electronic diary system. Other symptoms that were followed (some using the diary and others at clinic visits) included patient global impression of change (PGIC), sleep, fatigue, and mood.Ninety patients ultimately completed the trial, 32 in the milnacipran QD arm, 37 in the BID arm, and 21 placebo controls. In summary, 37% of patients taking 100 mg of milnacipran twice daily achieved a 50% reduction in pain compared to only 14% of patients on placebo. Furthermore, milnacipran dosed either once or twice daily, had beneficial effects upon PGIC, fatigue, and mood. Side effects including nausea and headache were mild and generally transient. The subgroup of patients with s diagnosable major depressive episode at the start of the trial bears specific mention. Overall, this group's response to milnacipran was similar to that of non-depressed patients; however, their placebo response rate was 33% compared to 5% in non-depressed patients.

A second dual uptake inhibitor, duloxetine—a DRI that, like venlafaxine, preferentially blocks the reuptake of 5-HT over that of NE— is also in clinical development, and the results of a phase II trial of duloxetine in FMS patients were recently announced.[192] This 12-week monotherapy study compared duloxetine dosed at 60 mg twice daily (120 mg/day) to placebo. Patients were escalated to the final dose over a 2-week escalation period, which followed a 1-week placebo run-in period. The primary outcome measures were the Fibromyalgia Impact Questionnaire (FIQ) total- and pain-subset scores.[192,235] Other measures included the PGIC, pain (via the Brief Pain Inventory), SF-36, and Quality of Life in Depression scale. A total of 207 patients completed the trial, 104 and 103 patients in the active and placebo arms, respectively. Overall, duloxetine treatment resulted in a significant improvement in total FIQ scores; however, changes in the FIQ pain score did not reach statistical significance. On the other hand, pain as measured by the Brief Pain Inventory was improved. No beneficial effects of duloxetine were noted on fatigue or sleep; indeed, insomnia was a significant side-effect of drug therapy. However, an improvement in mood was noted, as measured by the SF-36 and the Quality of Life in Depression scale.

Reboxetine, classified as a No repinephrine Reuptake Inhibitor (NERI) due to its selective inhibition of NE reuptake, is on the market as an anti-depressant in parts of Europe; however, it is currently unavailable within the US. A recent open-label trial of reboxetine in 25 FMS patients suggests this compound may be useful for treating pain and fatigue,[236] though more extensive follow-up studies are needed on this point. Another NRI—atomoxetine—has recently been introduced to the US market for the treatment of attention-deficit hyperactivity disorder ADHD). No data of the efficacy of this compound in pain are presently available. However, a randomized, double-blind, placebocontrolled trial in patients with chronic low back pain reported maprotoline—a tetra cyclic nora d renaline reuptake inhibitor (NARI)—to exhibit significantly greater efficacy than paroxetine at standard doses.[237] A different study, however, found maprotoline to be somewhat less effective than amitriptyline in the treatment of post-herpetic neuralgia. 207 Therefore, the results of limited empirical studies as well as scientific considerations lead one to assume that NARIs may exhibit better analgesic efficacy than the SSRIs, yet somewhat less efficacy than the TCAs and SNRIs which influence both monoamines.[238] Obviously, additional studies are required to confirm the role these agents will play in the treatment of chronic pain.

There are no published studies on the analgesic capabilities of nefazodone, a 5-HT2A receptor antagonist as well as a weak dual reuptake inhibitor. Animal studies have suggested that its 5-HT2 antagonism may be anti-nociceptive, due to increases in 5-HT1A mediated neuro-transmission. The clinical relevance of this has yet to be determined, especially since a related molecule, trazadone, has failed to exhibit significant analgesic effects when used for various pain conditions, including FMS.[239]

Mirtazapine is a potent central a2 autoreceptor antagonist as well as a 5-HT2 and 5-HT3 receptor antagonist with some anecdotal success as an analgesic.[240] While no controlled studies have been reported, mirtazapine's α2 autoreceptor mediated increases in NE (as well as 5-HT1A) neurotransmission and its ability to inhibit 5-HT3 (discussed below) may impart some anti-nociceptive activity.

Reversible Monoamine Oxidase Inhibitors (RIMAs). MAOIs increase monoamine levels by blocking their breakdown after release from the neuron, a mechanism distinct from TCAs, SSRIs, and DRIs. Non- enzyme- specific, irreversible, MAOI, such as phenelzine and tranylcypromine, have been on the market in the US for many years as antidepressants, though concerns about potentially fatal interactions with certain foods and medications have limited their widespread usage.[38] Moclebemide and pirlindole represent "second generation" agents that show improved specific and reversible binding compared to older compounds. Both of these agents have been approved in Europe as antidepressants, though they are not presently available within the US. Preliminary studies with moclobemide in FMS have failed to demonstrate significant analgesic activity when compared to amitriptyline.[206] However, a more recent study has demonstrated the efficacy of this compound in CFS, though effects were primarily limited to fatigue.[241] The results of a randomized, double-blind, placebo controlled trial of pirlindole in FMS were more promising, with beneficial effects upon sleep, pain, fatigue, and mood.[242] It is of interest to note that MAOIs show greater efficacy than TCAs in treating atypical depression, a particular depression subtype which is relatively common in patients with chronic pain conditions.[243]

Non-Steroidal Anti-Inflammatory Drugs. Non-steroidal anti-inflammatory drugs (NSAIDs; including COX-2-selective agents) and acetaminophen are used by a large number of FMS patients.[244] However, numerous studies have failed to confirm their effectiveness as analgesics in FMS, though there is limited evidence of patients experiencing enhanced analgesia when treated with combinations of NSAIDs and other agents.[188] This phenomenon may be a result of the painful, inflammatory conditions—including OA, rheumatoid arthritis, and lupus—being frequently comorbid with FMS.

The similarities between certain pathophysiological and biochemical mechanisms observed in epilepsy and neuropathic pain led to initial investigations of AEDs in chronic pain states.[245] Agents such as carbamazepine, lomotrigine, phenytoin, benzodiazepines, and gabapentin have been evaluated in neuropathic pain, and have been shown to have analgesic effects to varying degrees.[246] As a result, a number of drugs initially labeled as anti-epileptic agents are used regularly as analgesics.

The majority of AEDs increase the seizure threshold by reducing neuronal excitability through sodium and/or calcium channel blockades; this mechanism of action appears to underlie their analgesic activity as well.[246] Agents such as benzodiazepines, tiagabine, valproic acid, and topiramate also enhance GABAergic neuro transmission.[247] Therefore, although each specific agents' mechanism of action may differ, AEDs as a class generally reduce excitability, decrease ectopic discharge and reduce neurotransmitter release—effects which have been found to impart varying degrees of anti-nociceptive as well as antiepileptic activity.

The results of a phase II monotherapy trial investigating the use of pregabalin, an AED presently in clinical development, in the treatment of FMS were recently published.[248] Pharmacologically, pregabalin is thought to act by blocking certain calcium channels.[249] Three different doses of pregabalin—150, 300, and 450mg/day—were compared to placebo in this 8 week study. A total of 410 patients completed the trial—131, 103, 111, and 99 in the placebo, 150 mg, 300 mg, and 450 mg/day arms, respectively. The primary endpoint was pain, as measured by paper diary. Other endpoints included sleep, fatigue, and PGIC. In summary, 450 mg/day of pregabalin was found to result in a 50% pain reduction in 28.9% of patients, a significant difference vs. placebo (13.2%). In addition, sleep, fatigue, and PGIC measures all improved in patients in the 450 mg/day arm of the trial. Unfortunately, this high dose was also associated with a significant incidence of CNS side effects; dizziness, in particular was a problem in almost half of the patients taking this dose.

Carbamazepine and gabapentin have been approved as first-line therapies for trigeminal neuralgia and painful diabetic neuropathy, respectively, and the effectiveness of gabapentin in diabetic post-herpeticneuralgia has also been demonstrated.[250,251] Gabapentin is structurally and pharmacology similar to pregabalin; however, the gabapentin's efficacy has not formally been demonstrated in FMS. Other anti-convulsants, such as topiramate and lamotrigine, have received recent attention for their potential efficacy in neuropathic pain conditions.[238,246,252,253,254] However, no clinical evaluation of the effectiveness of these AEDs in FMS has been published, and the discouraging side effect profile of many of these agents has typically deterred their evaluation as front-line therapies.

Benzodiazepines are GABA agonists with analgesic actions in the spinal cord and brainstem of animal models,[255] as well as anti-epileptic properties as described above and muscle-relaxant properties as discussed below.While several uncontrolled studies have supported the benefit of clonazepam in neuropathic pain (specifically, trigeminal neuralgia), its use is compromised by side effects such as marked drowsiness or frank sedation.[256,257] In general, studies with other benzodiazepines in neuropathic pain have tended to be small and uncontrolled with inconsistant results.[258] The available data are also limited in FMS, but generally, these agents have been ineffective as analgesics.[259,260]

A handful of studies have been published on the use of certain nonbenzodiazepine hypnotics in FMS, such as zopiclone and zolpidem. These reports have suggested that, while improving patients' subjective sleep complaints, these agents do not improve the pain of FMS.[261,262,263]

Researchers have attempted to elucidate the relationship between circadian rhythms, melatonin secretion and FMS, but have produced inconsistent results.[128,129,264,265,266] Melatonin, available in the US as an unregulated dietary supplement, has been evaluated in one small open label pilot study involving 21 patients with FMS who were each given 3 mg of melatonin nightly for 30 days.While this study suggested possible benefits in sleep and tender point counts, melatonin did not appear to impact patients' overall levels of pain or fatigue.[264]

Gamma-hydroxybutyrate (GHB, also known as sodium oxybate) is a precursor of GABA with powerful sedative properties indicated for narcolepsy in the US. Of note, this compound has been reported to qualitatively improve sleep by increasing the quantity of slow wave sleep (SWS) and decreasing a-intrusion without significantly changing the quantity of REM sleep.[267] GHB was recently shown to be useful in improving fatigue, pain, and sleep architecture in patients with FMS in a pilot (18 patient) randomized, double-blind, placebo-controlled, crossover trial.[268] It is important to note, however, that several issues are likely to limit the widespread adoption of this compound. First, this agent is a controlled substance due to its abuse potential. Second, the short half-life of ã-hydroxybutyrate typically requires twice nightly administration, a dosing schedule that is likely to interrupt normal sleep architecture. Finally, the low potency of this compound (6 grams were used per night in the above trial) makes controlled-release dosage forms more difficult, as the drug is most practically formulated as a liquid.

Cyclobenzaprine is a muscle relaxant originally shown to be of some benefit in the management of fibromyalgia in the mid-1980s.[188] Although typically classified as a muscle relaxant, cyclobenzaprine shares structural and pharmacological similarities with TCAs.[193] The mechanism of action underlying cyclobenzaprine's muscle relaxing action is unclear, though it may be mediated by blockade of 5-HT2 receptors.[193] Data generally support its use in FMS, particularly in treating sleep and pain, and there are some data suggesting synergism when cyclobenzaprine is used with fluoxetine.[188,269] The major problems patients report with cyclobenzaprine are morning "hangover" and dry mouth. These issues may be alleviated to some degree by the use of lower doses of cyclobenzaprine (1 mg to 4 mg) which have recently been shown to improve pain, sleep, and fatigue in FMS patients.[270]

Tizanidine, an α2 adrenergic agonist, reduces muscle spasticity by increasing presynaptic inhibition of motor neurons, and has also demonstrated analgesic effects in animal pain models.[271,272] The anti-nociceptive properties of the α2 agonists are not surprising when one considers the multiple sites of α2 adrenergic receptors within both the ascending and descending pathways . For instance, α2 stimulation reduces activation of PAF terminals, thereby reducing Glu and SP release. Increased α2 stimulation within the RVM may also activate the descending 5-HT system, providing further anti-nociception. These agents may also directly inhibit dorsal horn projection neurons. A recent 8-week, open-label study of 25 fibromyalgia patients receiving a total daily dose of tizanidine of 4-24 mg reported significant improvements in several parameters, in cluding sleep, pain, and measures of quality of life.[273] Of particular interest is the demonstration that treatment with tizanidine results in a reduction in substance P(SP) levels within the cerebrospinal fluid (CSF) of patients with FMS.

Baclofen is a GABAB agonist also approved as an anti-spasticity agent and likewise documented to be aneffective adjuvant analgesic in the management of various types of neuropathic pain.[274,275,276] While its mode of action is not fully characterized, its analgesic effects may be due to suppression of dorsal horn neuronal activity. There are currently no data pertaining to the use of baclofen in patients with FMS.

Typical opiateagonists such as morphine act at various combinations of the mu, delta, and kappa opiate receptors. These receptors are located thoughout the CNS with all three receptors appearing to play a role in analgesia.[193] A recent study reported reduced levels of b-endorphin in peripheral blood mononuclear cells of fibromyalgia patients, implicating the possibility of a suboptimal endogenous in fibromyalgia patients.[277] Morphine and morphine-like compounds are widely used in many chronic pain states, including TMJD[278] and subsets of CLBP.[274] A survey of academic medical centers in the US reported that opiates were used in about 14% of FMS (mainly tertiary care) patients.[244]

There have been only a few controlled clinical trials of these agents in FMS. Interestingly, acutely administered intravenous morphine was not found to be effective in treating FMS pain.[280] Tramadol is another widely used analgesic that has a unique mechanism of action involving weak mu agonist activity combined with 5-HT/NE reuptake inhibition.[187] Three double-blind studies have demonstrated the efficacy and tolerability of tramadol in the management of fibromyalgia pain, as an isolated compound[281,282] and in fixed-dose combination with acetaminophen (ie, "Ultracet").[278]

5-T3 receptor antagonists (such as ondansetron and tropesitron), which are best known for their anti-emetic properties, also have analgesic effects.[284] Animal models have demonstrated that blockade of 5-HT3 receptors has both nociceptive and anti-nociceptive effects, and clinical trials in settings of chronic pain have repeatedly revealed a bellshaped dose response curve, suggesting that optimal analgesic effect may involve a dose-dependent balancing act between these opposing activities. This duality of effect may be due in part to the presence of 5-HT3 receptors on both PAF terminals and inhibitory dorsal horn interneurons.[284,285,286,287] This is an appropriate reminder of the complex nature by which the myriad 5-HT (and other) receptors interact throughout the pain pathways.

Members of the German Fibromyalgia Study Group extensively studied tropesitron in patients with FMS.[288,289,290,291,292] In addition to several small, open-label evaluations, a single randomized placebo-controlled doubleblind trial investigated the effectiveness of 5 mg, 10 mg, or 15 mg tropesitron given once daily for 10 days to 418 FMS patients. The results from this study suggest modest but statistically and clinically significant reductions in pain, but only in those patients treated with 5 mg tropisetron, consistent with the earlier described bell-shaped dose response curve. Constipation and other GI complaints were commonly reported, as is common with other 5-HT3 blockers.

As mentioned above, certain TCAs are known to be NMDA receptor antagonists, though their activity in this regard is relatively weak (ie, they are low affinity agents).[193] Three studies have demonstrated high-level NMDA receptor blockades (imparted by the use of high affinity agents or large doses of low affinity compounds) can improve pain symptoms in FMS patients.[280,294,295] However, such high-level blockades are associated with significant cognitive side-effects, thus potentially limiting the utility of this approach.While the search continues for agents with more tolerable side effect profiles, NMDA receptor antagonists may ultimately prove to be most beneficial as adjunctive therapies when used concomitantly with other analgesics.[290]

Considering the observation that SP levels within the CSF of patients with FMS are routinely elevated, drugs designed specifically as SP or NK1 receptor antagonists are theoretically attractive . Indeed, a doubleblind, placebo-controlled, randomized 8-week crossover study was conducted in 1994 to evaluate the use of a selective NK1 antagonist, CJ-119794, in the treatment of FMS.[296] In short , the results were disappointing; treatment with CJ-119794 resulted in no significant improvements in pain, sleep, or affective endpoints. Unfortunately, this result is rather consistent with NK1 antagonists in a variety of clinical settings, despite promising preclinical results.[97] The only notable exception to this general trend has been within the antiemetic indication, for which aripretant—also known as MK-0869—has recently received approval in the US.

Bennett et al. conducted a randomized , placebo-controlled , doubleblind study of the clinical effects of growth horm one (GH) therapy in 50 women with FMS and pre-determined low IGF-1 levels.[297] Patients we rerandomized to self-inject daily either GH or placebo (reconstituted excipient only) for 9 months. The dose of GH was adjusted to maintain blood IGF-1 levels at approximately 250 mg/ml. The GH-treated group achieved a significant improvement in pain, sleep, and fatigue scores at 9 months compared to baseline, whereas no significant improvement was observed in the placebo group. Patients' responses tended to lag behind the initiation of GH therapy by approximately 6 months, although measurable improvements in muscle strength and exercise performance were discernible after 3 months with progressive improvement there after. Since GH is known to raise energy levels, increase exercise capacity, build muscle strength, and improve cognitive function in other patient groups with decreased basal GH levels,[298,299,300,301] the improvements seen in this trial may merely reflect the general metabolic effects of GH and not be representative of a syndrome-specific response. Moreover, while GH therapy would appear to offer this subgroup of patients some symptomatic improvement, financial considerations limit the viability of GH as a long-term therapy in this population.

The two best studied non-pharmacological therapies are cognitive behavioral therapy (CBT) and exercise. Both of these therapies have been shown to be efficacious in the treatment of FMS, and excellent reviews of these treatments are referenced.[27,46,302] Both of these treatments can lead to sustained (eg, greater than one year) improvements and are very effective in compliant individuals. The challenge for new studies examining these treatments is to improve long-term adherence and compliance, and to move toward using modalities such as the Internet, or telemedicine, that will allow a larger number of patients access to these therapies. Also, new studies need to address the optimal manner in which to combine pharmacologic and non-pharmacologic therapies.

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