Fibromyalgia Syndrome: Can It Be Treated?

Fibromyalgia syndrome (FMS) is a chronic, painful, and sometimes disabling condition commonly encountered by primary care physicians. Recent research has provided information about the pathophysiology of FMS that has implications for treatment. For example, it now seems most likely that the major pathophysiologic mechanisms of FMS involve central sensitization in the CNS, although a peripheral source of nociception may initiate and/or perpetuate this sensitization. Thus, drugs that act through the CNS (such as tricyclic agents, selective serotonin reuptake inhibitors [SSRIs], and tramadol) are more likely to be effective than those that act primarily at a peripheral level-for example, NSAIDs. The same CNS mechanism may also explain why hypnotherapy or meditation may be beneficial in FMS.

Understanding pathophysiologic mechanisms, as discussed in our article in the September 1, 2003, issue,¹ is important for treating disease. Although the mechanisms in FMS are incompletely understood at this time, the relevant factors for treatment purposes include central sensitization (amplified or perpetuated by poor sleep); psychological distress; peripheral pain generators (eg, overuse of body parts, repetitive trauma, and arthritis); deconditioning; and other aggravating factors (eg, weather, noise, and comorbid conditions).

The management of FMS has been reviewed in detail.²Key components of treatment are shown in Table 1. We will describe each of these below.

POSITIVE AND EMPATHETIC ATTITUDE OF THE PHYSICIAN

The management of FMS begins with the very first contact with the patient. Many patients with aches and pains have had an unhelpful or even unpleasant experience with their previous health care providers, or heard of such experiences from their friends. Greeting a patient in a friendly and positive manner goes a long way to assure that you are a kind and interested physician. Maintain such an attitude of caring throughout the period of consultation and subsequent follow-ups.

MAKING A FIRM DIAGNOSIS

As we emphasized in our previous article,¹ FMS should be diagnosed by its own characteristic features of widespread pain and multiple tender points, and not by "ruling out" other conditions, as stated in the American College of Rheumatology (ACR) criteria.¹ Ordering one more test to exclude such and such disease may cause anxiety, since such an approach is not only unnecessary, it may also indicate uncertainty on the part of the physician, and thus erode a patient's confidence in him or her.

PATIENT EDUCATION, REASSURANCE, AND INDIVIDUALIZATION OF TREATMENT

After the diagnosis is made, patient education is a most important step. Provide information to patients with FMS, in a simple, understandable way regarding the diagnosis and probable cause, aggravating factors (Table 2), and prognosis, and then use Table 1 to discuss various elements of management. Emphasize that a patient's pain and other symptoms are "real" and based on a "chemical imbalance," such as excessive substance P and decreased serotonin. However, reassure your patient that FMS is not life-threatening (despite much pain), and that it does not cause tissue damage. (We avoid using the term "benign" because patients who are suffering may resent it.) Advise on general healthy behavior, including weight loss, smoking cessation, good sleep habits, and regular exercise. Also emphasize the need for both nonpharmacologic and pharmacologic therapy. A recent study has found an association between overweight and several important FMS features, such as fatigue, decreased physical function, and increased number of tender points.³Smoking is positively associated with pain, global severity, and functional difficulties.⁴

Tailor your management according to each patient's symptom profile. For example, some patients may have significant psychological distress, while others have a predominant sleep problem, and yet others have specific aggravating factors, such as poor sleep, repetitive trauma (vocational and recreational), and mental stress. Some patients cope with their symptoms fairly well, while others do not. Although FMS is a chronic painful condition, emphasize that most patients find relief with appropriate treatment for a period of time, and that during this time they can be meaningfully functional.

ADDRESSING AGGRAVATING FACTORS

Aggravating factors that should be addressed are listed in Table 2. The importance of physical fitness (in the context of deconditioning) will be described in detail under "Nonpharmacologic Intervention."Other important factors will be discussed here. Note that treatment of concomitant hypothyroidism does not eliminate FMS symptoms, but it may help relieve fatigue and low energy.

Psychological factors. Psychological distress is correlated with pain, including pain in FMS.⁵ Thus, psychological factors, such as anxiety, stress, depression, and poor coping, should always be addressed. Stress is an important factor in both triggering and perpetuating FMS symptoms. Besides counseling for psychological difficulties, anxiolytics and antidepressants in appropriate doses may be required. SSRIs are as effective as tricyclic agents for depression and have fewer side effects. If necessary, refer patients to a psychologist for stress reduction or to a psychiatrist for refractory anxiety and depression.

Improving sleep quality. Nonrestorative sleep exacerbates pain and fatigue. Poor sleep at night predicts pain the next day.⁶ Take a good sleep history and offer suggestions for improved sleep quality (Table 3). Morning fatigue is a sensitive indicator of nonrestorative sleep. Restless legs syndrome and/or periodic limb movement disorder is an important cause of sleep disturbance and is treatable with medications (see "Pharmacologic Management").

Environmental factors. Depending on individual sensitivity to specific weather factors, advise your patients to avoid unnecessary outside trips in the winter and to stay in comfortable temperature in an air-conditioned room in the summer as much as possible. Many patients are also sensitive to noise, smell, and light. Hyperresponsiveness to many of these environmental stimuli, as well as to many medications, is thought to be attributable to central sensitization.¹

Occupational factors. Prolonged sitting or standing at work, adverse ergonomic factors that cause muscle or other soft tissue strain, repetitive motion, and job stress and dissatisfaction may all contribute to FMS symptoms. Based on current knowledge of pain physiology, repetitive motions are likely to cause central sensitization¹ and subsequent amplification and intensification of pain. Because an important goal of treatment of FMS is to keep the patient employed, both for psychological and economic reasons, these work-related aggravating factors should be discussed with the employer, along with appropriate recommendations, such as change of duties and improvement of adverse ergonomic conditions.

Comorbid conditions. Although this theory has not been directly proved in patients with FMS, current knowledge of central sensitization operative in FMS suggests that any continued source of peripheral nociception enhances this sensitization and worsens pain. Thus, arthritis of any kind, neuropathy, or headaches should be treated. Restless legs syndrome disturbs sleep (Table 2).

Family and social factors. Adverse family circumstances, such as a stressful marriage, demanding children, and a lack of empathy and understanding by family members, can add significant distress. This, in turn, may aggravate pain, fatigue, and other associated symptoms, such as headaches and migraine. However, excessive attention from a solicitous spouse may also adversely affect a patient's pain.⁷ Refer your patient to a psychologist for assistance with coping skills, if needed. Encourage patients to have a hobby and a network of support.

NONPHARMACOLOGIC APPROACH

When primary care physicians inquire about FMS treatment, they commonly ask,"I have used such and such medications without success. What should I try next?" This is unfortunate, since nonpharmacologic approaches, including patient support and education (Table 1), are an essential component of FMS therapy and should be used in parallel with drug treatment with equal emphasis. Often physicians do not optimally utilize nonpharmacologic therapies. Patients who use both nonpharmacologic and pharmacologic therapies have better results than with either modality alone.⁸

Physical fitness. Many patients with FMS are deconditioned. Several controlled studies have shown the benefits of regular exercise in ameliorating FMS symptoms, including pain.⁹ However, randomized, controlled studies that did not preselect patients based on their ability to engage in exercises did not demonstrate such benefit. I think the reason is obvious: it is difficult for most FMS patients to exercise vigorously enough to achieve cardiovascular fitness. But some exercise is better than none for overall health benefit, and it is important to be persistent in encouraging and monitoring a patient's exercise at every office visit. We emphasize that in the phrase "regular exercise," regular is more important than exercise. It is the habit of initiating an exercise every day that is crucial.

We insist that patients keep a daily diary of their physical activities, preferably in graphic form (how much time spent and the peak pulse rate) and bring the weekly graphs for our inspection during the next visit. We encourage our patients by saying that everyone can exercise. The key is to start slowly-for example, only 2 to 3 minutes of exercise a day, if need be. Ask patients to gradually increase the exercise time, say by 2 to 3 minutes each week, to the ideal 20 to 30 minutes of brisk exercise every day. Treadmill or outdoor walking, aerobic dancing, and swimming are excellent forms of exercise, depending on patient preference. Muscle strengthening exercises, started gradually as above, are useful in reducing the effort needed to do a given task, and are likely to lessen fatigue.

Physical therapy. No controlled data exist to show that physical therapy by itself helps patients with FMS. However, clinical observation suggests that a subgroup of patients report significant benefit from such therapy for a few days. Physical therapy modalities include local heat (moist or dry), ultrasound, stretching, range of motion exercises, muscle strengthening exercises, manipulation, and correction of posture. After initial demonstration by a therapist, many of these modalities may be used by a patient at home regularly.

Electromyographic biofeedback. Current data on the efficacy of electromyographic (EMG) biofeedback alone are contradictory. However, if facilities are available, this modality may be prescribed along with other important forms of therapy, such as education, exercise, and medication. Some patients may benefit if they can be persuaded to try EMG biofeedback for at least 4 months or longer.

Acupuncture and transcutaneous electrical nerve stimulation (TENS). One double-blind controlled study has shown the benefit of electroacupuncture in FMS over a 3-week period.¹⁰ Long-term studies are needed. Appropriate studies showing the efficacy of conventional acupuncture or TENS are lacking. Some patients report benefit, but others report aggravation of pain from acupuncture or TENS therapy.

Cognitive behavioral therapy and multidisciplinary treatment. Cognitive behavioral therapy(CBT) involves training patients in coping skills, healthy behavior patterns, and restructuring of maladaptive beliefs, such as catastrophizing ("I have a serious disease like cancer, and I may die of it") or significant pessimism ("My symptoms are killing me and I will never get better. I cannot do exercise; I cannot do anything"). Although a few nonrandomized studies using waiting list controls demonstrated the benefit of CBT in FMS,¹¹ two well-designed randomized investigations using attention controls (who received adequate patient education regarding FMS and its management, but without structured comprehensive CBT) demonstrated no benefit in the group that used CBT (which is time-consuming and expensive) compared with the control group.^12,13

We have found that some-but not all- "difficult" FMS patients (those who did not respond to usual treatment) whom we referred to a competent psychologist for CBT derived some benefit. However, one may argue that CBT should be started early (particularly in those showing poor coping skills during the initial consultation) rather than late, before maladaptive behaviors become ingrained.

Instead of recommending multidisciplinary treatment in a group setting under one umbrella, we individualize care and refer patients to an appropriate facility (physical therapy, exercise, CBT, etc) as needed. Multidisciplinary treatment is expensive and often not covered by insurance and, because of the group setting, does not focus on an individual patient's concerns. Its value is yet to be determined by randomized, double-blind controlled studies.

Hypnotherapy. One controlled study has shown the benefit of hypnotherapy in "refractory" FMS.¹⁴ We believe hypnotherapy is worth trying in an otherwise nonresponsive patient if a competent therapist is available.

Meditation. In an open but otherwise well-designed study, weekly supervised meditation for 10 weeks was impressively beneficial in more than half of patients.¹⁵ Patients were also required to meditate daily for 50 minutes at home. In practice, however, patients may not be willing to comply with such a time-consuming regimen.

PHARMACOLOGIC TREATMENT

Drug treatment is as important as nonpharmacologic therapy. Randomized, double-blind, controlled studies have shown the efficacy of several drugs in FMS; however, long-term data are not available. Because evidence-based medicine is appropriately emphasized in current medical practice, agents with clinically demonstrated efficacy should be tried first. We then use other drugs in the same class (eg, tricyclic agents other than amitriptyline) that have a similar mode of action, despite the fact that these drugs may not have been studied in controlled trials. Like any treatment modality, drug therapy needs to be individualized, depending on symptom severity, comorbid psychiatric or "organic" diseases, sleep difficulties, and history of side effects. Drug treatment in FMS has been reviewed.²

Simple analgesics. Simple analgesics, such as acetaminophen, may be prescribed for patients with mild or mild to moderate pain. NSAIDs were ineffective in several studies of patients with FMS.² However, these agents may be used for concomitant conditions, such as arthritis and dysmenorrhea, with the usual precautions.

Table 4 lists the centrally acting drugs that have been found useful or effective in FMS, including those that were studied in controlled trials. Their dosages and common side effects are also listed.

Tricyclic agents. These drugs are reuptake blockers of both serotonin and norepinephrine, neurotransmitters that are implicated in the inhibitory pathway of pain physiology. Amitriptyline^2,16 and cyclobenzaprine^2,17 are the most widely used, based on their demonstrated efficacy in several studies.² A lower dose of amitriptyline than that used in depression is effective in FMS. The usualdose is 25 to 50 mg at bedtime. In patients who have side effects at 25 mg, start with a lower dose, ie, 10 mg, and gradually titrate to 50 to 75 mg at bedtime.

Common adverse reactions include grogginess, dry mouth, daytime sleepiness, weight gain, and paradoxical insomnia. Cardiac arrhythmias, mostly associated with tricyclic antidepressants, occur rarely; use caution in prescribing these agents in patients with heart disease and in elderly persons. Cyclobenzaprine, a drug related to the tricyclics but without antidepressant properties, is as effective as amitriptyline and has similar side effects. The long-term efficacy of tricyclic agents in FMS is not known.

SSRIs. Fluoxetine alone at an average dose of 55 mg/d was effective in most outcome measures in a double-blind, randomized, controlled study of women with FMS.¹⁸ A similarly controlled study of a combination of fluoxetine, 20 mg in the morning, and amitriptyline, 10 to 25 mg at bedtime, found that this combination was significantly more effective than either drug alone in relieving both pain and poor sleep.¹⁹ Studies have shown that a drug with both serotonergic and noradrenergic properties works better in chronic pain.

Remember, the dose of a tricyclic drug, when used in combination with an SSRI (particularly fluoxetine), should be kept low to avoid serious drug interactions resulting in tricyclic overdose; blood tricyclic level should be checked if such an interaction is suspected. Other SSRIs shown in Table 4 have not been studied in FMS, but anecdotal observation supports their benefit, particularly in combination with a low-dose tricyclic agent (10 to 50 mg at bedtime).

Other antidepressant medications. Many patients in our clinic have reported benefit from venlafaxine, trazodone, and nefazodone, but controlled studies are lacking.

Other centrally acting drugs. Tramadol, like cyclobenzaprine, is a centrally acting drug without antidepressant properties. It is a reuptake inhibitor of serotonin and norepinephrine, but it also binds weakly with µ-opioid receptors. Although reports of addiction are rare, tramadol should not be prescribed in patients with a history of drug (including alcohol) abuse. Tramadol was effective in a randomized, double-blind controlled trial of patients with FMS.²⁰ In our practice, we prescribe 400 to 800 mg/d in divided doses with food. Smaller doses should be tried first and increased to the optimal dose, because adverse reactions (such as GI effects, dizziness, and somnolence) are common.

Note that drugs with demonstrated efficacy in randomized, double-blind studies are not all antidepressants, which suggests that depression is not synonymous with FMS. Moreover, tricyclic antidepressants have a direct central analgesic effect in FMS irrespective of their effect on depression.¹⁶

Medications for associated symptoms. Hypnotic agents are useful for induction of sleep, but not for sleep maintenance or pain.² Tricyclic agents are a better choice for restorative sleep in patients with FMS. Associated significant anxiety and depression should be adequately treated with anxiolytic agents (such as alprazolam) and antidepressants; remember that a larger dose of antidepressants is required than the low dose prescribed for FMS symptoms alone. For restless legs syndrome, there are several choices (all taken at bedtime)²¹:

•Clonazepam, 0.5 to 2 mg.

•Carbidopa-levodopa, 25 to 100 mg, 1 or 2 tablets on an empty stomach.

•Opioids (eg, codeine, 30 to 60 mg).

•Caveats include an increase in restless legs syndrome in the afternoon associated with carbidopa-levodopa and the potential abuse of codeine.²¹

TENDER POINT INJECTIONS

In an open study, injections of tender point sites were useful, with a median relief period of 3 months.²² We ask our patients to localize their most symptomatic sites with their own fingertips first and then we confirm those sites by palpation for injection. We use a 27-gauge 1-inch long needle and 1% or 2% lidocaine, 0.25 to 0.50 mL, usually in no more than 4 or 5 (typically 2 to 4) sites. Make sure that the needle does not penetrate tissues beyond the muscles, to avoid such complications as pneumothorax.

Studies of myofascial syndrome suggest that the addition of corticosteroids has no advantage over lidocaine alone.²² Even dry needling is useful, although it is more painful than injection of a local anesthetic. Such injections may work by stimulating the local pain inhibitory neurons, probably "desensitizing" the state of central sensitization in FMS, which may explain why the benefit lasts beyond the local anesthetic effects.²³ Remember, the success of a tender point injection depends not only on the injection itself, but also "physician effect" (positive attitude, support, encouragement).²²

WHAT ABOUT NARCOTICS?

Whether narcotics may be used in benign pain conditions such as FMS or osteoarthritis (OA) is a contentious issue among physicians. A double-blind, randomized controlled study of oxycodone (10 to 20 mg every 12 hours) in OA demonstrated its efficacy and relative safety over a period of 12 months.²⁴

We use narcotics quite uncommonly, and only when other management components have failed. We have found oxycodone, 10 to 30 mg/d in divided doses every 12 hours, and acetaminophen, 300 mg, with codeine, 30 mg, 2 to 4 times a day, beneficial. We use opioids mostly during a flare-up, but they may be continued long-term provided no side effects or abuse emerge.

Although, theoretically, short-acting opioids may have a greater potential to induce addiction, we have not encountered such a problem in our practice. The key is to select patients carefully. A history of addiction or alcohol or drug abuse is a contraindication, and patients must be monitored regularly for drug-seeking behavior. Another caveat based on recent studies is that opioids can paradoxically increase sensitivity to pain in some persons. A patient who seems to need higher doses after some time may benefit from a decreased dose.²⁵

COMPLEMENTARY AND ALTERNATIVE MEDICINE

Complementary and alternative medicine (CAM) in FMS has been reviewed.²⁶ It remains, for the most part, unproved in FMS. A large number of studies on St John's wort have yielded contradictory results. This herb product cannot be confidently recommended at this time because of a lack of standardization in various manufacturers' products; its potential serious interactions with other antidepressants, particularly SSRIs; and its ineffectiveness in severe depression.

S-adenosylmethionine (SAM-e) is a naturally occurring compound that, at a dose of 400 mg bid, significantly improved pain, fatigue, and mood in a randomized, double-blind controlled study involving 44 FMS patients.²⁷ GI symptoms are the most common side effects, and an interaction with other antidepressants may occur. We have found SAM-e beneficial in a few of our patients.

Static magnetic therapy also relieved pain over a period of 6 months in a randomized, double-blind controlled study.²⁸ We have not used this therapy so far, but it is worth trying in consultation with an expert in this area.

There are limited studies on CAM in FMS, but for general information, the review by Crofford and Appleton²⁶ is useful.

The Figure shows a general pyramidal approach to FMS management. Note that tender point injections may be used at any stage of treatment and opioid therapy is kept at the top rung of the pyramid.

PROGNOSIS

Although follow-up studies of patients with FMS show no significant fluctuations over a period of several years,² these studies have not evaluated symptoms frequently, for example, every 1 to 2 weeks. Our observations suggest that most patients experience significant relief with therapeutic interventions over a period of 2 to 12 weeks (sometimes longer), during which time they are also meaningfully functional. In a minority of patients, such relief may be sustained long-term. Thus, appropriate management is important.

References:

REFERENCES:

1. Arslan S, Yunus MB. Fibromyalgia: making a firm diagnosis, understanding its pathophysiology. Consultant. 2003;43:1233-1244a.

2. Inanici F, Yunus MB. Management of fibromyalgia syndrome. In Rachlin ES, Rachlin IS, eds. Myofascial Pain and Fibromyalgia: Trigger Point Management. Philadelphia: Mosby; 2000:33-55.

3. Yunus MB, Arslan S. Relationship between body mass index and fibromyalgia features. Scan J Rheumatol. 2002;31:27-31.

4. Yunus MB, Arslan S. Relationship between fibromyalgia features and smoking. Scand J Rheumatol. 2002;31:301-305.

5. Dailey PA, Bishop GD, Russell IJ, Fletcher EM. Psychological stress and the fibrositis/fibromyalgia syndrome. J Rheumatol. 1990;17:1380-1385.

6. Affleck G, Urrows S, Tennen H, et al. Sequential daily relations of sleep, pain intensity, and attention to pain among women with fibromyalgia. Pain. 1996; 68:363-368.

7. Romano JM, Turner JA, Friedman IS, et al. Sequential analysis of chronic pain behaviors and spouse responses. J Consult Pain Clin Psychol. 1992; 60:777-782.

8. Leventhal LJ. Management of fibromyalgia. Ann Intern Med. 1999;131:850-858.

9. McCain GA, Bell DA, Mai FM, Halliday PD. A controlled study of the effects of a supervised cardiovascular fitness training program on the manifestations of primary fibromyalgia. Arthritis Rheum. 1988;31:1135-1141.

10. DeLuze C, Bosila L, Zirbs A, et al. Electroacu- puncture in fibromyalgia: results of a controlled trial. BMJ. 1992;305:1249-1252.

11. Williams DA, Cary MA, Groner KH, et al. Improving physical functional status in patients with fibromyalgia: a brief cognitive behavioral intervention. J Rheumatol. 2002;29:1280-1286.

12. Vlaeyen JW, Teeken-Gruben NJ, Goossens ME, et al. Cognitive-educational treatment of fibromyalgia: a randomized clinical trial, I: clinical effects. J Rheumatol. 1996;23:1237-1245.

13. Nicassio PM, Radojevic V, Weisman MH, et al. A comparison of behavioral and educational interventions for fibromyalgia. J Rheumatol. 1997;24: 2000-2007.

14. Haanen HC, Hoenderdos HT, van Romunde LK, et al. Controlled trial of hypnotherapy in the treatment of refractory fibromyalgia. J Rheumatol. 1991;18:72-75.

15. Kaplan KH, Goldenberg DL, Galvin-Nadeau M. The impact of a meditation-based stress reduction program on fibromyalgia. Gen Hosp Psychiatry. 1993; 15:284-289.

16. Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum. 1986;29:1371-1377.

17. Bennett RM, Gatter RA, Campbell SM, et al. A comparison of cyclobenzaprine and placebo in the management of fibrositis. A double-blind controlled study. Arthritis Rheum. 1988;31:1535-1542.

18. Arnold LM, Hess EV, Hudson JI, et al. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112:191-197.

19. Goldenberg D, Mayskiy M, Mossey C, et al. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia. Arthritis Rheum. 1996;39:1852-1859.

20. Russell IJ, Kamin M, Bennett RM, et al. Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin Rheumatol. 2002;6:250-257.

21. Silber MH, Restless legs syndrome. Mayo Clin Proc. 1997;72:261-264.

22. Reddy SS, Yunus MB, Inanici F, Aldag JC. Tender point injections are beneficial in fibromyalgia syndrome: a descriptive, open study. J Musculoskel Pain. 2000;8:7-18.

23. Baldry P. Superficial dry needling at myofas- cial trigger point sites. J MusculoskelPain. 1995;3: 117-126.

24. Roth SH, Fleischmann RM, Burch FX, et al. Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain: placebo-con-trolled trial and long-term evaluation. Arch Intern Med. 2000;160:853-860.

25. Mao J. Opioid-induced abnormal pain sensitivity: implications in clinical opioid therapy. Pain. 2002; 100:213-217.

26. Crofford LJ, Appleton BE. Complementary and alternate therapies for fibromyalgia. Curr Rheumatol Rep. 2001;3:147-156.

27. Jacobsen S, Danneskiold-Samsoe B, Andersen RB. Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scan J Rheumatol. 1991;20:294-302.

28. Alfano AP, Taylor AG, Forseman PA, et al. Static magnetic fields for treatment of fibromyalgia: a randomized controlled trial. J Altern Complement Med. 2001;7:53-64.

29. Yunus MB. Fibromyalgia syndrome: is there any effective therapy? Consultant. 1996;36:1279-1285.