Long-term efficacy of spironolactone on pain, mood, and quality of life in women with fibromyalgia: An observational case series

2.2.1 The fibromyalgia impact questionnaire (FIQ)

This established and validated instrument assesses physical functioning, days felt good, pain, morning tiredness, fatigue, stiffness, anxiety, and depressive mood [10]. Each item ranges from 0 to 10 score points, the first two items address the status after normalisation. The composite index of the FIQ comprises a total score from 0 to 80 without cut-off due to the wide-range of FMS. This simple measure is sensitive to change, meaningful, easy to handle, cheap, applicable to all patients, and quickly evaluated by clinical practitioners. FIQ’s disadvantage is that the time frame only covers the last week.

2.2.2 Emotional functioning

Emotional functioning was assessed by a German self-report multidimensional mood questionnaire BSKE (EWL) [11]. This questionnaire contains 8 items to describe positive mood dimensions, and 10 items reflecting negative mood states. Responders rated each item from 0 (not at all) to 6 (very strong) indicating the level during past four weeks. The sums of the respective items give the total score, for positive mood ranging from 0 to 48, and for negative mood from 0 to 60. There was also one addendum item as a brief index of “perceived stress” related to workplace, family, partner, interpersonal conflicts, and environmental factors. It was rated on the same seven point scale.

2.2.3 Additional measures regarding mental and physical domains

Because the multidimensional mood questionnaire contains important issues of interest which could selectively strengthen the evidence of changes on any treatment, four items were calculated separately: concentration, lack of energy, fatigue (day time), and feeling drowsy. Due to the difficulties of applying additional lengthy validated questionnaires in clinical practice, further important psychophysical and bodily complaints were presented as written items which had to be answered on seven point ordinal scales scored from “never (0) to always (6)” for the past four weeks. The questions are worded: restorative sleep, bodily weakness/exhaustion, forgetfulness, muscle tension, and dizziness.

2.2.4 Further appropriate indicators of change

At the endpoint of the study, patients were asked to assess the global impression of improvement, rated on a transition scale anchored: 1 = very much worse, 4 = unchanged, and 7 = very much improved. Another set of questions was used to confirm and specify the spectrum of changes more detailed over the whole treatment period by the items: (1) improvement in health related quality of life; (2) increase in physical activity; (3) amelioration in mobility and endurance; (4) reduction in pain; (5) intake of concurrent medications and (6) frequency of visiting medical practitioners or specialists during the observation period. These items were rated as percentage of changes compared to the baseline condition.

2.2.5 Changes in medication

The number of different drugs was counted and the change of this number was given as percentage value. This mode of pharmaco-therapeutic recording (irrespective of the daily dosages) of analgesics during chronic pain syndromes is considered as an objective procedure.

2.3.1 Pharmacokinetics of spironolactone

It is quickly cleared from plasma after oral intake with a mean elimination half life (t_1/2) of 1.4 h, whereas the active metabolites 7α-thiomethylspironolactone, 6β-hydroxy-7α-thiomethylspironolactone, and canrenone had t_1/2 values of 13.8, 15, and 16.5 h, respectively [12].

3.5.1 Prediction of efficacy

A rapid onset of response within a few days according to what the patients have reported to the physician at the first follow-up-visit, has proven as the best predictor for long-term efficiency, whereas severe emotional disturbances at baseline, appeared to characterise poor or non-responders (data not shown).

Some women achieved an early improvement in activity level, sleep and fatigue on lower dosage, but acceptable pain relief requested a dosage ≥100 mg/day. Abrupt discontinuation of drug (during a travel abroad) exacerbated pain in two women.

3.5.2 Duration of effect

Six responsive patients have been followed for six years, one for over 12 years. They adhered to spironolactone without loss of activity or side effects apart from transient hyperkalemia in one woman.

3.5.3 Weight reduction in obese patients

The majority of FMS patients suffered from a variety of other diseases either representing a family of medical and psychiatric disorders with a common pathophysiology [14] or general medical diseases not related to FMS (see Table 1). Overweight or obesity is frequently associated with FMS. Indeed, this was also true for seven cases (47% of 15 patients). The weight loss in patients ranged from 1.1 kg to 9.8 kg (mean 2.6 ± 2.2 kg) at the third visit.

3.5.4 Clinical hyperandrogenism and hypertension

Hirsutism, acne or alopecia, typical symptoms of hyperandrogenism [15,16] were improved in five women, hypertension was lowered in five women, and two patients showed improvements in both symptoms.

3.5.5 Antimigraine effect

It is noteworthy that four (out of 15) patients with concomitant migraine, one of them with a history of 30 years, did not suffer from headache attacks during the observation period and beyond.

3.5.6 Restless legs syndrome

One woman experienced complete and sustained reduction of restless legs syndrome and leg cramps and could abstain from levodopa. The omission of levodopa supports our hypothesis, that the beneficial actions of spironolactone might also involve increase in dopamine effects (see Section 4).

3.5.7 Anxiolytic effect

The same woman did not experience any more her frequent panic attacks associated with the hyperventilation syndrome.

3.5.8 Eating disorders

Two patients with binge eating disorder (BED), possibly related to persistent pain and negative affectivity, had lost eating abnormalities under spironolactone already at the 6-months visit. This normalisation in eating behaviour remained stable throughout the observation period and was documented by an eating disorder inventory. The co-occurrence of FMS with eating disorders [17] has already been recognised earlier.

4.2.1 Effects on GABA transmission

Spironolactone blocks mineralocorticoid and androgen receptors dose-dependently, and has agonistic activity on progesterone receptors. In contrast to the peripheral endocrine effects, the mechanisms of actions of spironolactone in the central nervous system (CNS) are incompletely understood. Mineralocorticoid receptors (MR) as primary target on spironolactone express highest density in the septo-hippocampal area [23,24]. Inhibition of these receptors by spironolactone, or synthetic analogues, administered either systemically or intraventricularly, provokes a variety of behavioural and molecular changes in rodents, e.g. anxiolytic [25] and anticonvulsant effects. Furthermore, cognitive dysfunctions induced by the anticholinergic drug scopolamine, were markedly antagonised [26].

FMS is a complex syndrome with apparent dysregulation of several body systems, mainly in the brain. Interestingly, spironolactone has also been shown to act directly on the membrane-bound γ-aminobutyric acid (GABA) – receptor complex [27]. Based on endocrinological studies in man [28,29], spironolactone enhances the circulating levels of deoxycorticosterone and progesterone. Their naturally occurring 3α,5α-reduced metabolites (3α,5α-tetrahydroprogesterone [3α,5α THP] and 3α,5α-tetrahydrodeoxycorticosterone [3α,5α THDOC]), both generated by enzymes in various tissues including brain [30], were shown to enhance GABAergic transmission [31]. These metabolites, also termed neuroactive steroids (neurosteroids), exert a broad spectrum of behavioural changes including sedative, hypnotic, anxiolytic, anti-aggressive, anticonvulsant, and sleep modulating effects in animals and humans [32]. THP or THDOC administration to rats reduces plasma corticosterone levels in response to stress. Thus, these neurosteroids attenuate the function of hypothalamic-pituitary-adrenal (HPA) axis possibly by GABAergic action in the hypothalamus [33] which suppresses sympathetic overactivity, too. THP and the synthetic 3α-5α neuroactive steroid alphaxalone effectively alleviate thermal and mechanical hyperalgesia in a rat model of neuropathic pain [34].

Furthermore, the 3α-reduced neurosteroids modulate depressive behaviour and realise the action of antidepressants [35,36,37]. Thus, animal research provides strong evidence that spironolactone can increase the GABAergic transmission with consequent attenuation of central pain responses [38]. Moreover, it increases the presence of neuroactive steroids which in turn attenuates central stress responses and enhances anxiolysis or sedation.

Besides the improvement in emotional functioning by GABAergic mechanisms, GABA activation plays a well known predominant role in the amelioration of restorative sleep disturbances. Interestingly, that reinforcement of GABA transmission positively affects the slow wave pattern [39], which is one established abnormality in patients with FMS [40]. Non-restorative sleep is discussed as the common denominator for multiple somatic and mental complaints and is rated as an FMS-aggravating factor in 79% of patients (n = 2596) based on an internet survey [41].

4.2.2 Effect on dopamine transmission

In FMS-patients, levels of dopamine (DA) metabolites are reduced in the cerebrospinal fluid [42] and PET studies have confirmed the hypo-dopaminergic state in FMS [43]. In line with this observation, hypo-dopaminergic alterations reflect prolonged stress, a distinct feature of FMS-patients [44,45,46]. We speculate that the GABA activation by the anti-mineralocorticoid itself, its sulphur containing metabolites, or by induced release of neurosteroids might also affect the dopaminergic system. Both, GABA and the neurosteroid THP (also called allopregnanolone) reinforce the dopaminergic system and antagonise anti-dopaminergic effects [47,48,49,50]. Thus, a decreased GABAergic tone associated with low DAergic activity could be defined as a further neurobiological characteristic at least in a subgroup of women with FMS. It is tempting to speculate that the inactive GABA-dopamine-axis contributes to pain perception and emotional dysfunction as well as to dyscognition, perception speed, and memory dysfunction, often referred to as “fibro-fog”.

4.2.3 Effects on the nociceptive system

Recent observations have reported a pro-nociceptive role of an activation of the mineralocorticoid-receptor (MR) in the pathogenesis of painful diabetic polyneuropathy [51] whereas MR blockade by the MR antagonist eplerenone reduces pain behaviour and decreases excitability in small-diameter sensory neurons [52] Spironolactone was found to elevate the concentration of morphine fourfold in the brain, and it was hypothesised that spironolactone inhibits the outward-directed P-gp transporter [53]. A substantial subset of FMS patients show symptoms of small-fibre polyneuropathy (SFPN) [54,55], and it is a challenging hypothesis to test whether spironolactone might affect clinical aspects of SFPN.

4.2.4 Clinical observations of spironolactone related to FMS

Spironolactone has already been studied to treat tension headache and migraine, however, there are no reports on chronic pain disorders [56]. Already 35 years ago, mood stabilisation was seen in 5 of 6 patients with bipolar disorder on spironolactone treatment (100 mg daily) between 12 and 18 months without any side effects [57]. In women suffering from premenstrual syndrome (PMS) during 14 premenstrual days, a placebo controlled trial demonstrated a significant decrease in negative emotions such as anxiety and tension, irritability, fatigue and depression, whereas the positive affect indices were increased comprising cheerfulness, well-being, friendliness, and feeling energetic [58]. Older conference abstracts reported on mood enhancing as well as stress tolerance improving effects of spironolactone as documented in hyperandrogenised women (J. Niemeyer; medical thesis 1996; University of Würzburg; no electronic version available).

Finally, prolonged stress is often associated with hypocortisolemia and diminished adrenal responsiveness despite hyperactive ACTH release [59], that sometimes is found in FMS patients. Interestingly, inhibition of central MR by spironolactone elevates the plasma cortisol levels in healthy adults [60], and these effects might help to normalise the decreased adrenal responsiveness in FMS-patients. Moreover, activation of central MR under chronic stress conditions attenuates serotonin release and turnover, and this can be reversed by MR inhibition [60].

Spironolactone has a proven safety profile, and it has beneficial metabolic [61], cardiovascular [62] and anti-inflammatory [63] effects. It could be an option for those patients with various symptoms such as dyscognition (“fibro-fog”) and psychological distress. Spironolactone might not only improve pain syndromes in FMS, but also further symptoms in overlapping conditions of the so called “central sensitivity syndrome” [8] such as tension and migraine headache, restless legs syndrome, and pre-menstrual syndrome (PMS).