© U.S. Cancer Pain Relief Committee, 2001 0885-3924/01/$–see front matterPublished by Elsevier, New York, New York PII S0885-3924(01)00302-5

704 Journal of Pain and Symptom Management Vol. 22 No. 2 August 2001

Clinical Note

Olanzapine for the Treatment ofFibromyalgia Symptoms

R. Sanford Kiser, MD, Howard M. Cohen, MD, Robert N. Freedenfeld, PhD, Carolyn Jewell,RN, MSN, and Perry N. Fuchs,PhD

Texas Pain Medicine Clinic (R.S.K., H.M.C., R.N.F., C.J.), Dallas, and Department of Psychology (P.N.F.), University of Texas at Arlington, Arlington, Texas, USA

Abstract

Fibromyalgia is a chronic condition that is diagnosed primarily by the presence of generalized pain along with tenderness on palpation of certain body regions. Unfortunately, the pharmacological treatment of fibromyalgia remains problematic. Two patients are described who highlight the use of the atypical neuroleptic olanzapine for the control of symptoms related to fibromyalgia. Prior to the use of olanzapine, both patients had received a multitude of treatments, none of which greatly improved their ability to function in daily activities. With olanzapine, both patients reported a significant decrease in pain and marked improvement in daily functioning. In one case, the pain returned during a period of time when olanzapine was discontinued, an effect that was reversed when olanzapine was reintroduced. The paucity of serious side effects (i.e., extrapyramidal signs) with the atypical neuroleptic olanzapine strongly favors further exploration and use of this drug for the treatment of fibromyalgia symptoms.

J Pain Symptom Manage 2001;22:704–708. ©

U.S. Cancer Pain Relief Committee, 2001.

Key Words

Fibromyalgia, neuroleptic, atypical neuroleptic, Zyprexa

Introduction

Fibromyalgia is an enigmatic illness. Its etiol-ogy is obscure, and effective treatment is elu-sive. This condition is often diagnosed by thecriteria of the American College of Rheumatol-ogy, which rely primarily on the presence ofgeneralized pain, along with tenderness on pal-pation at 11 of 18 body points. Unfortunatelythis diagnostic approach can have limitations,

1

and fibromyalgia symptoms can overlap withsymptoms of other conditions, thus creatingcontroversy about the diagnosis of fibromyal-

gia, and even doubt about whether it exists as adiscrete illness.

2,3

The treatment of fibromyalgia, not surpris-ingly, has also been problematic. Clinicianshave struggled to find an effective means oftreatment. Common interventions have in-cluded physical therapy and conditioning,psychological counseling, patient education,trigger point injections, and medication thera-pies.

3,4

Pharmacological interventions havehad only limited success. These treatmentshave generally included antidepressant drugssuch as amitriptyline,

5

muscle relaxants such ascyclobenzaprine,

6

and a variety of nonsteroidalanti-inflammatory agents.

7

Although some newpharmacological approaches appear promis-ing,

7

no reliable drug treatment exists. Herein,we report 2 patients who demonstrate that the

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R. Sanford Kiser, MD, TexasPain Medicine Clinic, Suite 200, 5327 N. Central Ex-pressway, Dallas TX 75205, USA.

Accepted for publication: October 31, 2000.

Vol. 22 No. 2 August 2001 Olanzapine and Fibromyalgia 705

atypical neuroleptic medication olanzapinecan have dramatic and sometimes definitivebenefit for fibromyalgia.

Case 1

A 50-year-old married white female had ahistory of fibromyalgia and a past history ofsurgical treatment for temporomandibularjoint pain. She had previously been diagnosedwith recurrent major depression and dys-thymia. Multiple families of antidepressantsand anticonvulsants had been tried with inter-mittent improvements in mood, but with nosignificant improvement in pain. She had alsoused tramadol, various benzodiazepines, andseveral muscle relaxants, with only moderatebenefit for pain. A previous trial of haloperidolfor persistent insomnia and acute thought dis-order, characterized by mild tangentialthought processes and periodic ideas of refer-ence, was discontinued as a result of akathisia.It had not helped her pain symptoms. The pa-tient underwent treatment in a multidisci-plinary pain program, which improved herability to function and diminished her depres-sive symptoms. However, she continued to re-port pain that significantly limited her daily ac-tivities. Her medication regimen at completionof the program included trazodone 150 mg atbedtime, clonazepam 6 mg at bedtime, anddaily as-needed use of baclofen and tramadolfor pain control.

Due to the treatment resistant nature of herfibromyalgia pain, a trial of olanzapine 5 mg atbedtime was initiated at a time when the pa-tient’s thought disorder was in remission. Atthree-month follow-up, she reported signifi-cant reduction in daily aching pain symptoms.She had reduced use of baclofen and tramadolto times of extended vigorous physical activity.A troubling side effect of the olanzapineemerged as gradual weight gain. She discontin-ued the olanzapine and began a trial of an-other atypical neuroleptic, quetiapine. Wewere hoping for similar pain relief without theweight gain. After gradually titrating the doseup to 100 mg at bedtime, we found this medi-cation had no benefit for her pain symptoms,and she requested to restart the olanzapine.Again she experienced significant pain im-provement, and was able to keep her weightunder control with diet and vigorous aerobic

exercise. Due to improvement in insomniawith the olanzapine, she was able to graduallytaper the clonazepam to 2 mg at bedtime.

Case 2

A 53-year-old married white male presentedto our clinic with a history of treatment-resis-tant fibromyalgia. His history also includedpsoriatic arthritis, temporomandibular jointsyndrome, failed back syndrome and periodicepisodes of gout. He also had a below the kneeleg amputation secondary to an accidental gunshot wound. At times, he had elevated liver en-zymes that were correlated with doses of meth-otrexate prescribed for arthritis by his rheuma-tologist. He had been disabled for 20 years,and prior treatments with several trials of tricy-clic and selective serotonin reuptake inhibitor(SSRI) antidepressants and benzodiazepineswere without benefit for depression, anxiety,or pain. At the time of initial evaluation, he wastaking paroxetine 20 mg at bedtime, trazodone150 mg at bedtime, cyclobenzaprine 10 mgthree times a day, carisoprodol 350 mg everysix hours as needed, furosemide 20 mg fourtimes a day, zolpidem 10 mg at bedtime, al-lopurinol 300 mg daily, cetirizine 10 mg at bed-time, and oxycodone/acetaminophen 2 to 3pills daily as-needed for pain.

The patient was started on a trial of olanzap-ine 10 mg at bedtime. He noted significant im-provement in pain after starting the drug, andwas able to discontinue the oxycodone/ace-taminophen. Because of complaints of persis-tent irritability and depression, the paroxetinedose was increased to 40 mg daily. Treatmentwith tramadol was substituted for the oxyc-odone/acetaminophen. He reported muchimprovement in mood and insomnia at his fol-low-up visit one month after starting olanzap-ine, but reported a 10-pound weight gain dur-ing that time. He was gradually able to reducehis cyclobenzaprine use to only an as-neededbasis. Over the course of three months, hemaintained the pain improvement, but no-ticed consistent carbohydrate cravings, with aneventual 27-pound weight gain that necessi-tated a resizing of his leg prosthesis. Despitethe extra weight he elected to continue olanza-pine treatment due to the major pain improve-ment and his enhanced daily functioning. For-mal pain ratings were taken at intake and 12

706 Kiser et al. Vol. 22 No. 2 August 2001

months after beginning olanzapine. At intake,he indicated that 10 out of 10 queried body re-gions were in pain, with pain ratings varyingbetween 3/10 and 7/10 among these variousregions. At 12 months, he reported that only 4out of 10 body regions were in pain, with painratings varying between 1/10 and 2/10.

Discussion

These two cases are representative of a num-ber of our treatment-resistant fibromyalgia pa-tients who have benefited from the atypicalneuroleptic olanzapine. In our experienceolanzapine can have a focused and potent ef-fect on fibromyalgia symptoms. Though thereare no literature reports of treating fibromyal-gia with atypical neuroleptics, other authorshave described using older neuroleptics totreat various pain disorders, with mixed suc-cess. There have been previous case reports ofthe treatment of persistent and severe fibromy-algia with the neuroleptic chlorpromazine.

8

Inaddition, there have been case reports of neu-roleptics being used for various pain syn-dromes, such as the treatment of neuropathicpain with fluphenazine given in combinationwith a tricyclic antidepressants,

9

and the treat-ment of generalized pain with pimozide.

10

Methotrimeprazine has been marketed fortreatment of generalized pain in hospitalizedpatients.

11

A major disadvantage of these olderneuroleptics has been their potential for seri-ous side effects including tardive dyskinesia, se-dation, anticholinergic problems, and extrapy-ramidal symptoms.

Olanzapine is an atypical neuroleptic thathas been shown to be beneficial for schizo-phrenia, psychosis, bipolar disorder, and possi-bly other affective disorders.

12

An advantage ofatypical neuroleptics such as olanzapine is amore favorable side effect profile, particularlyinvolving less tardive dyskinesia and extrapyra-midal dysfunction. In contrast to older neuro-leptics, which are characterized by greaterdopaminergic receptor blockade (as well asother neurotransmitter effects that are gener-ally believed responsible for side effects), olan-zapine’s mechanism of action is thought to beprimarily due to highly selective D2 and 5HT-2antagonism.

13

Both classes of neurolepticsshare antihistaminic, muscarinic, alpha-adren-ergic, and other neurotransmitter effects that

have not traditionally been thought to producerelief for fibromyalgia, pain, or depression.Our first patient failed a treatment of haloperi-dol and was exquisitely sensitive to its dopamin-ergic receptor blocking effects. It is thereforepossible that olanzapine’s unique combinationof D-2 selective receptor antagonism and 5HT-2antagonism effects can benefit a subset of pa-tients with severe fibromyalgia, perhaps thosewith a genetic predisposition. Interestingly,treatment with quetiapine, an atypical neurolep-tic with similar but quantitatively different ef-fects on multiple receptors, was not beneficial inthe case of patient 1. This raises the question ofwhat novel qualities olanzapine might havecompared to quetiapine, which can account forpain relief. For instance, it is known that com-pared to olanzapine, quetiapine has relativelylower D-2 antagonism effects and relativelymuch lower 5HT-2 antagonism effects.

14

There are many theories of fibromyalgia eti-ology, but none seem to adequately explainthe complex of symptoms or the responses tovarious treatments. Recent theories of fibromy-algia hypothesize that it is triggered in geneti-cally predisposed individuals by unknowninfectious, rheumatologic, psychoneuroendo-crine, immunologic, or traumatic processes, orother causes of central nervous system irritabil-ity.

15

Various investigators have shown evi-dence of serotonergic

16

and substance P

17

neu-rotransmitter dysregulation, as well as evidencefor intramuscular dysregulation of adenosinetriphosphate metabolism

18

and deficiencies inneural regulation.

19

Fibromyalgia has alsobeen viewed as a member of a family of syn-dromes that cluster together that might haveheritable factors. These syndromes include af-fective disorders, chronic fatigue syndrome, in-terstitial cystitis, temporomandibular syn-drome, and irritable bowel syndrome.

15

Due to the lack of a coherent understandingof fibromyalgia etiology, a variety of treatmentshave been explored. Aerobic exercise

20

andvarious pharmacologic attempts to treat fibro-myalgia have been only partially effective andhave failed to help many patients. Pharmaco-logic approaches using tricyclic antidepres-sants and cyclobenzaprine have been the mostwidely studied treatments. Although some pa-tients benefit from other types of antidepres-sants, such as venlafaxine

21

and the SSRI par-oxetine,

22

other SSRIs, including fluoxetine

23

Vol. 22 No. 2 August 2001 Olanzapine and Fibromyalgia 707

and citalopram,

24

have not been found to beclearly effective. It has been difficult to sub-stantiate a hypothesis for disturbed serotoninfunction as an etiology for fibromyalgia, sincepatients have benefited from some serotonin-enhancing medications and not from others.On the other hand, fibromyalgia patients havebeen shown to experience pain relief benefitfrom treatment with the 5HT-3 antagonist on-dansetron.

18

It is possible that fibromyalgiasymptom improvement from medications af-fecting the serotonergic system may be due tosecondary effects related to yet unidentifiedneurotransmitters. More study is needed inthis area since evidence for serotonin involve-ment in pain control is significant, but detailshave not been clearly elucidated.

25

In Case 1, olanzapine was clearly helpful inreducing the patient’s fibromyalgia symptoms.This was strikingly demonstrated when the pa-tient suffered a relapse of her pain symptomswhen olanzapine was discontinued and im-provement when the medication was resumed.Additionally, the patient had clearly failedtreatment for fibromyalgia pain with multipleantidepressants. Most of these antidepressantshad been only marginally beneficial for her de-pression as well. The patient’s response toolanzapine did not appear to be a result oftreatment of her depressive syndrome, as thosesymptoms varied independently of her paincomplaints. Interestingly, she had a familialpattern for fibromyalgia, as her daughter alsosuffered from a recalcitrant fibromyalgia syn-drome, but while her daughter’s depressivesymptoms responded to SSRIs, olanzapine didnot help her pain symptoms.

In Case 2, olanzapine had a strong effect inreducing the patient’s fibromyalgia symptoms.This was shown by the dramatic reduction inhis pain symptoms and the significant increasehe reported in overall functioning at his fol-low-up appointment. He appeared to experi-ence further benefit in symptoms of pain anddepression when the paroxetine dose was in-creased. However, the paroxetine use hadbeen long-standing, and pain had not re-sponded to it and other multiple SSRIs previ-ously. He described clear and pronouncedpain relief following institution of olanzapineprior to the increase in paroxetine dose. Thusit was clear that his response to his pain syn-drome improvement was not associated with

an increase in the paroxetine dose. This pa-tient also had a strong family history of fibro-myalgia and depression syndromes, as hisbrother suffered from similar symptoms.

This report describes two of several fibromy-algia patients treated at our pain clinic over thepast several years who have benefited fromolanzapine when other medications havefailed. We feel that further study of olanzap-ine’s use with fibromyalgia patients is neededdue to the significant effects we have seen. Tosubstantiate these findings and establish itsmode of function, we need rigorously designedprospective studies investigating its pain reliev-ing effectiveness, which could rule out otherexplanations for this benefit. Other interestingresearch could explore whether olanzapinehas primary analgesic actions or whether its ac-tion is due to more general effects on a hypoth-esized fibromyalgia symptom complex. For ex-ample, it would be important to study whethersymptom improvement is due primarily toolanzapine’s effects on fibromyalgia-relatedsymptoms, such as depression, insomnia, andfatigue. Such studies would include prospec-tive clinical trials in a crossover fashion with abaseline medication wash-out period. We alsoencourage investigations of yet unknown andpotentially useful pharmacologic effects ofolanzapine other than its documented effectsin the treatment of psychotic disorders, whichcould account for the observed pain relief. Forexample, unknown actions of olanzapine mightelucidate one or more of several alternative the-ories for the etiology of the fibromyalgia syn-drome such as Arnold–Chiari malformation

26

and infections.

27

In summary, this paper highlights our expe-rience that some fibromyalgia patients, whosesymptoms have been resistant to a wide rangeof interventions, can improve with olanzapinetreatment. The resulting reduction in pain anddisability has allowed them to resume morenormal lives. We believe that this dramatic ben-efit calls for further investigations into the va-lidity of our observations and the possible ac-tions of olanzapine.

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