Pregabalin Augmentation of Quetiapine Therapy in the Treatment of Fibromyalgia: An Open-Label, Prospective Trial

• Abstract
• Introduction
• Methods
• Patients
• Design and outcomes
• Data analysis
• Results
• Discussion
• References

Abstract

Introduction: Quetiapine has been shown to improve fibromyalgia symptoms, especially sleep disturbance, fatigue, morning stiffness, and mental well-being, but lacks an effect on pain. The purpose of this study was to evaluate if pregabalin, which has shown antialgic activity in fibromyalgia, added to quetiapine treatment additionally improved fibromyalgia symptomatology.

Methods: This was an open-label, 12-week study. Pregabalin was administered to 19 female fibromyalgia patients at a starting dose of 75 mg/day subsequently adjusted in according to the drug's efficacy and tolerability. Outcome measures included the Fibromyalgia Impact Questionnaire (FIQ), the Pittsburgh Sleep Quality Index, the Beck Depression Inventory, the State and Trait Anxiety Inventory, and the SF-12 Health Survey.

Results: Data analysis was done on the Intention-To-Treat sample which included 18 patients. Pregabalin significantly improved the pain and tiredness after awakening subscales of the FIQ as well as the physical component of the SF-12. Six patients withdrew from the study, 3 because of side effects.

Conclusions: Our results suggest that the use of pregabalin can be a useful augmentation strategy in fibromyalgia patients partially responding to quetiapine.

Introduction

Fibromyalgia is a chronic syndrome characterized by widespread pain and muscle tenderness frequently accompanied by distressing symptoms such as fatigue, morning stiffness, sleep disruption, cognitive dysfunction, anxiety and depression [17]. It is generally assumed that it is a complex and difficult to treat disorder, which usually requires a multidisciplinary approach using both pharmacological and non-pharmacological interventions [10] [17]. Regarding the former, no drug has been specifically approved for fibromyalgia by the US Food and Drug Administration nor by the European Medicines Agency [2]. However, several drugs have been investigated and found effective in controlled clinical trials; among them, tramadol, cyclobenzaprine, tricyclic antidepressants, new dual serotonin and noradrenalin reuptake inhibitors, and, more recently, pregabalin and pramipexole [2] [5] [6] [13]. Also, an open label trial has shown the efficacy of mirtazapine, an antidepressant which acts by blocking both 5-HT₂ and presynaptic alpha-adenergic receptors [19].

Although drug monotherapy would be the optimum treatment approach, the multidimensional nature of this syndrome and its high comorbidity with other disorders like chronic migraine, temporomandibular disorder, irritable bowel syndrome, and chronic fatigue syndrome [1] often leads to the use of polypharmacy. Therefore, combination therapy using drugs targeting different symptoms of the disease seems to be worthy of exploration. However, very few studies have been done to evaluate the efficacy of combination therapy in fibromyalgia treatment. Fossaluza and De Vita [9] found that cyclobenzaprine associated with ibuprofen was slightly more effective than cyclobenzaprine alone. Goldenberg et al. [10] showed that amitriptyline combined with fluoxetine worked better than either antidepressant alone, and Bennett et al. [4] observed that tramadol plus acetaminophen was better than placebo.

New antipsychotics, which are substantially better tolerated than the older ones [14], may have analgesic properties [8]. In a previous work [12] we found that quetiapine, a second generation antipsychotic with sleep-improving and antidepressant properties, substantially ameliorated fibromyalgia symptomatology, decreasing significantly both Fibromyalgia Impact Questionnaire (FIQ) total score and Pittsburgh Sleep Quality Index (PSQI) score, and increasing significantly the mental subscore of the SF-12 Health Survey (SF-12). Additionally, the drug showed significant antidepressant and anxiolytic activity. Concerning specific FIQ subscores, however, although moderate to large effect sizes were observed on fatigue (0.72), stiffness (0.55), and number of days felt good (0.92), the effect of quetiapine on the pain FIQ subscore was scarcely relevant (0.29).

Pregabalin is a new anticonvulsant drug which has also been licensed for the treatment of neuropathic pain and generalized anxiety disorder. Similar to gabapentin, it acts as a ligand on the α₂δ subunit of type P/Q calcium channels [3]. In a recently published double-blind, placebo-controlled trial [6], it has been shown to improve fibromyalgia symptoms, decreasing specifically and significantly pain scores at the study end point when administered at a dosage of 450 mg/day; lower doses of 150 and 300 mg/day, however, did not ameliorate fibromyalgia pain although the 300 mg/day dosage significantly improved fatigue and sleep quality.

Given the above-mentioned considerations, the purpose of the present open label study was to assess if pregabalin, administered as add-on drug to fibromyalgia patients previously receiving quetiapine and improved under this treatment, was able to provide additional amelioration of fibromyalgia symptomatology.

Methods

Patients

The sample comprised nineteen female patients, aged from 34 to 60 years (47±7) who had been receiving quetiapine for at least the previous six months in doses ranging from 25 to 100 mg/day (76±27), and reported improvement under this drug: in a Patient Global Impression of Improvement Scale (PGI) one patient reported very much improvement, nine much improvement and nine reported mild improvement. However, all of them still complained of relevant symptomatology, showing a score of at least 4 in the pain subscale of the FIQ (mean score: 7.82±2.13). Patients were excluded if they had previously received pregabalin or if they had known hypersensitivity to pregabalin or any of its ingredients. Every patient provided written informed consent to participate and the study was approved by the Ethics Committee of the University of Granada (Spain).

Design and outcomes

This was an unicenter, open-label, flexible dose study of 12 weeks of duration. Pregabalin was added to the treatment at an initial dosage of 75 mg/day, which was subsequently adjusted at follow-up visits according to the drug's efficacy and tolerability. Assessment measures included the Fibromyalgia Impact Questionnaire (FIQ), the Pittsburgh Sleep Quality Index (PSQI), the Beck Depression Inventory (BDI), the State and Trait Anxiety Inventory (STAI), and the SF-12 Health Survey (SF-12), all of which were administered at baseline and at different subsequent visits as detailed below. The SF-12 is a general indicator of health status in adults. It is a derivative of the Medical Outcomes Study SF-36, and produces a mental component summary (MCS) and physical component summary (PCS).

At week 2, a telephone contact was made to perform the first dose adjustment and to ascertain whether any tolerability issue had arisen. Patient follow-up visits were scheduled for weeks 4, 8 and 12. Patients were evaluated at each of these visits using the FIQ and a Patient Global Impression of Improvement (PGIi). In addition, BDI, STAI, PSQI and SF-12 were administered at the study endpoint. Treatment-related adverse reactions were recorded at each study visit by an open question.

The primary efficacy measures were the mean change from baseline to endpoint in the FIQ total score (ranging from 0 to 80) and in the subscores 4 to 10 which are visual analogue scales (VAS). Secondary outcome measures were the changes from baseline to endpoint in the scores of PSQI, BDI, STAI (state-anxiety and trait-anxiety), and SF-12 (physical and mental components).

Data analysis

The intention-to-treat (ITT) sample included those patients who were prescribed pregabalin and had at least one post-baseline efficacy evaluation. Analysis of the intention-to-treat sample was performed with the last observation carried forward approach (LOCF). All effectiveness analyses were based on the ITT sample. The significance of within group changes from baseline to endpoint in the total scores or subscores of the efficacy scales were calculated with Student's t test for paired data; they were considered significant if the p value was less than 0.05. No correction for multiplicity was applied. In order to interpret clinical relevance of changes in those efficacy scales, the effect sizes (ES) were also calculated as mean change in score (before and after treatment) divided by the standard deviation of the same measure before treatment [16]. For interpreting the relative magnitude of the change we considered an effect size of ±0.20 as small, one of ±0.50 as moderate and one of ±0.80 or greater as large.

Results

The nineteen included patients constituted the tolerability sample. Overall, six (31.6%) patients withdrew from the study before its endpoint. Two of them because of adverse drug reactions, one because of lack of efficacy, one because of adverse reactions plus lack of efficacy, and two were lost to follow-up. The ITT sample comprised 18 patients. The quetiapine and final pregabalin daily doses are shown in [Table 1].

Our sample had a high degree of comorbidity: nineteen (100%) patients had temporomandibular dysfunction, seventeen (89.5%) suffered chronic migraine, 15 (78.9%) tension-type headache, and nine (47.4%) irritable bowel syndrome. Despite the improvement experienced under quetiapine treatment, patients had a baseline mean FIQ pain subscore of 7.87±2.08, indicating a high degree of disability.

As it can be seen in [Table 2], total FIQ scores showed a non-statistically significant decrease, and a small effect size (0.35) was observed. Among the FIQ subscores both pain (0.58) and tiredness after awakening (0.69) showed moderate effect sizes even if only the pain subscore reached statistical significance. Among secondary outcome measures ([Table 3]), the decrease in depression and in state-anxiety scores were statistically significant but the effect size was small whereas the trait anxiety score showed no change. No changes were seen in sleep quality. The physical component of the SF-12 increased significantly while the mental component of SF-12 did not vary.

According to the PGIi, at study end, four (30.8) of the thirteen completers reported to be much or very much improved and six (46.1%) reported to be mildly improved; eight of them asked to continue with the quetiapine plus pregabalin combination.

Tolerability was generally good. Only 3 (15.8%) patients withdrew due to treatment-related adverse events. The most frequent adverse reactions were dizziness (31.6%), light-headedness (26.3%), dry mouth (15.8%), and weight increase, somnolence, blurred vision, incoordination and vertigo with a frequency of 10.5% each. Most of the reported side effects, were transient, so that the 76.9% of the completers finished the study free of side effects.

Discussion

Pregabalin augmentation of quetiapine therapy significantly improved pain and quality of life. However, the mean reduction observed in total scores of the FIQ was only of 5.27 points, clearly lower than the decrease observed previously with quetiapine which was of 10.2 points [12]. However, it must be taken into account that pregabalin acted upon patients whose symptoms were already ameliorated by quetiapine. On the other hand, it is important to emphasize that pregabalin reduced two subscores of the FIQ which were not improved under quetiapine: pain and tiredness after awakening. Crofford et al. [6] have demonstrated that pregabalin is an effective drug for the treatment of patients with fibromyalgia. Our results reinforce the usefulness of pregabalin in these patients and add the possibility that pregabalin may also play a role as an augmentation agent. It is worthy of mention that in our study pregabalin doses were substantially lower than the 450 mg/day required to reduce pain severity in the above-mentioned study. Perhaps this was due to its combination with quetiapine but the data of our study do not allow to us test this possibility.

Pregabalin did not improve sleep quality or relieve depression and anxiety, either in the BDI and STAI scores as well as in the FIQ subscales. To a certain extent, our data are not consistent with pregabalin's spectrum of activity, since it has shown efficacy in randomized clinical trials in the treatment of generalized anxiety disorder [15]. However, it must be stated that most of our patients received doses of pregabalin lower than 300 mg/day ([Table 1]), and that the only two clinical trials evaluating lower doses (150 mg/day) of pregabalin in the treatment of generalized anxiety disorder yielded contradictory results, one of them finding moderate anxiolytic activity for this dosage [18] and the other one finding it not superior to placebo [7]. On the other hand, it must be also taken in account that anxiety, depression and especially sleep quality were already significantly improved during the previous quetiapine treatment.

Overall, the main purpose of our study was to see if the pregabalin added to quetiapine could additionally improve fibromyalgia symptomatology, especially in those areas where quetiapine was not useful as is the case of body pain and physical well-being. The observed decrease in the pain subscore of the FIQ and the increase in the physical component of the SF-12 indicate that this was just the case. However, it must be stated that our sample was constituted by patients who were previously responders to quetiapine and who by no means can be considered representative of the general fibromyalgia population. Additionally, our sample was comprised of patients with high comorbidity including several painful comorbid conditions. Whether the benefit observed in our study was partially due to an improvement in these concomitant conditions cannot be ruled out. Finally, it must be stated that the sample's size was small and it was an open-label study. All of these limitations restrict the interpretation and generalization of the data. Still, they seem suggestive that a potentiation may exist between quetiapine and pregabalin which could be of benefit at least to some fibromyalgia patients, with both drugs acting upon different domains of the fibromyalgia spectrum of symptoms, so that the action of each drug could be complementary.

As stated before, the two trials which compared combination therapy with monotherapy in fibromyalgia found that the former was more effective than the later. Fossaluza and De Vita [9] observed that improvement in morning stiffness was significantly higher in the ibuprofen plus cyclobenzaprine group than in the group receiving cyclobenzaprine alone. Goldenberg et al. [10] found that the combination of amitriptyline and fluoxetine was significantly better that either antidepressant alone in FIQ total score, pain, general well-being and sleep disturbance. Although our study suggests that pregabalin could potentiate and/or complement the beneficial effects observed with quetiapine, whether the combination of quetiapine and pregabalin as initial therapy would be better that either drug alone is a question that deserves further testing.

References

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Correspondence

E. P. Calandre

Elena Pita Calandre

Instituto de Neurociencias

Avenida de Madrid 11

18012 Granada

Spain

Phone: +34/958/24 62 91

Fax: +34/958/24 35 37

Email: calandre@gmail.com

References

• 1 Aaron LA, Buchwald D. Chronic diffuse muskuloskeletal pain, fibromyalgia and comorbid unexplained medical conditions.  Best Pract Res Clin Rheumatol. 2003;  17 563-574
  CrossrefPubMedSearch in Google Scholar
• 2 Arnold LM. Biology and therapy of fibromyalgia. New therapies in fibromyalgia.  Arthritis Res Ther. 2006;  8 212 DOI: doi:10.1186/ar1971 , (Epub ahead of print)
  CrossrefPubMedSearch in Google Scholar
• 3 Ben Menachem E. Pregabalin pharmacology and its relevance to clinical practice.  Epilepsia. 2004;  45 13-18
  PubMedSearch in Google Scholar
• 4 Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia: a double-blind, randomized, placebo-controlled study.  Am J Med. 2003;  114 537-545
  CrossrefPubMedSearch in Google Scholar
• 5 Crofford LJ. Pharmaceutical treatment options for fibromyalgia.  Curr Rheumatol Rep. 2004;  6 274-280
  PubMedSearch in Google Scholar
• 6 Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ, Dworkin RH, Corbin AE. et al . Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial.  Arthritis Rheum. 2005;  52 1264-1273
  CrossrefPubMedSearch in Google Scholar
• 7 Feltner DE, Crockatt JC, Dubovsky SJ, Cohn CK, Shrivastava RK, Targum SD. et al . A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder.  J Clin Psychopharmacol. 2003;  23 240-249
  CrossrefPubMedSearch in Google Scholar
• 8 Fishbain DA, Cutler RB, Lewis J, Cole B, Rosomoff RS, Rosomoff HL. Do the second generation “atypical neuroleptics” have analgesic properties? A structured evidence-base review.  Pain Med. 2005;  5 359-365
  PubMedSearch in Google Scholar
• 9 Fossaluza V, De Vita S. Combined therapy with cyclobenzaprine and ibuprofen in primary fibromyalgia syndrome.  Int J Clin Pharm Res. 1992;  12 99-102
  PubMedSearch in Google Scholar
• 10 Golbenberg D, Mayskiy M, Mossey C, Ruthazer R, Schmid C. A randomized, double-blind crossover trial of fluoxetine and amitriptyline in the treatment of fibromyalgia.  Arthritis Rheum. 1996;  39 1852-1859
  PubMedSearch in Google Scholar
• 11 Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome.  JAMA. 2004;  292 2388-2395
  CrossrefPubMedSearch in Google Scholar
• 12 Hidalgo J, Rico-Villademoros F, Calandre EP. An open-label study of quetiapine in the treatment of fibromyalgia.  Prog Neuropsychopharmacol Biol Psychiatry. 2007;  31 71-77
  CrossrefPubMedSearch in Google Scholar
• 13 Holman AJ, Myers RR. A randomized, double-blind, placebo-controlled trial of pramiprexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications.  Arthritis Rheum. 2005;  52 2495-2505
  CrossrefPubMedSearch in Google Scholar
• 14 Karow A, Schnedler D, Naber D. What would the patient choose? Subjective comparison of atypical and typical neuroleptics.  Pharmacopsychiatry. 2006;  39 47-51
  Thieme ConnectPubMedSearch in Google Scholar
• 15 Kavoussi R. Pregabalin: from molecule to medicine.  Eur Neuropsycho-pharmacol. 2006;  16 128-133
  CrossrefPubMedSearch in Google Scholar
• 16 Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status.  Med Care. 1989;  27 178-189
  CrossrefPubMedSearch in Google Scholar
• 17 Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment.  J Rheumatol. 2005;  32 6-21
  PubMedSearch in Google Scholar
• 18 Pande AC, Crockatt JC, Feltner DE, Janney CA, Smith WT, Weisler R. et al . Pregabalin in generalized anxiety disorder: a placebo-controlled trial.  Am J Psychiatry. 2003;  160 533-540
  CrossrefPubMedSearch in Google Scholar
• 19 Samborski W, Lezanska-Szpera M, Rybakowsky JK. Open trial of mirtazapine in patients with fibromyalgia.  Pharmacopsychiatry. 2004;  37 168-170
  Thieme ConnectPubMedSearch in Google Scholar

Correspondence

E. P. Calandre

Elena Pita Calandre

Instituto de Neurociencias

Avenida de Madrid 11

18012 Granada

Spain

Phone: +34/958/24 62 91

Fax: +34/958/24 35 37

Email: calandre@gmail.com