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Treatment of pain in fibromyalgia patients with testosterone gel: Pharmacokinetics and clinical response
Abstract and Figures
To test our hypothesis that testosterone deficiency plays an important role in chronic pain, a Phase I/II pilot study was initiated with 12 fibromyalgia patients to verify that a daily dose for 28days with transdermal testosterone gel would 1) significantly and safely increase mean serum testosterone concentrations from low baseline levels to mid/high-normal levels, and 2) effectively treat the pain and fatigue symptoms of fibromyalgia. Pharmacokinetic data confirmed that serum free testosterone concentrations were raised significantly above baseline levels, by assessment of maximum hormone concentration (Cmax) and area under the curve (AUC) parameters: free testosterone Cmax was significantly raised from a mean of 2.64pg/mL to 3.91pg/mL (p<0.05), and 24hour free testosterone AUC was significantly raised from a mean of 35.0pg-hr/mL to 53.89pg-hr/mL. Assessment of the typical symptoms of fibromyalgia by patient questionnaire and tender point exam demonstrated significant change in: decreased muscle pain, stiffness, and fatigue, and increased libido during study treatment. These results are consistent with the hypothesized ability of testosterone to relieve the symptoms of fibromyalgia. Symptoms not tightly related to fibromyalgia were not improved.
Copyright © 2015. Published by Elsevier B.V.
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... Interestingly, within this group, the prevalence of FM was significantly lower in subjects taking contraceptive therapy [21]. On the contrary, a small study carried out on healthy young women showed that, assuming contraceptive treatment eliminates the cyclic hormonal fluctuation of the induced pain, without reducing the number of tender points or the entity of the perceived pain overall [22][23][24][25][26][27][28][29]. We reported a case of a 31 years old female affected by deep endometriosis, which developed FM symptoms soon after the interruption of the continuous hormonal contraceptive treatment and that recovered after the HC treatment was restarted. ...
... As a result, it is reasonable to consider a protective role of testosterone in the development of the disease. Accordingly, a pilot study conducted over 12 subjects affected by FM, which investigated the therapeutic action of transdermal testosterone gel, showed a significant reduction of the pain and fatigue symptoms, proportionally to the increase of the serum testosterone concentration serum[24]. Curiously, while FM is more prevalent in women, its' incidenceincreases after the menopause and the childbirth, when the sexual hormones abruptly declines. This suggests an ambivalent role of female sexual hormones in the syndrome, that may act in pleiotropic ways and the possible protective role of a slightly fluctuating hormonal concentration. ...
... Interestingly, post-hoc analyses evaluating the correlation between cortisol and sex hormones, classifying steroid levels as high, medium, or low, showed that progesterone correlation with pain was only significant at high levels of cortisol, meaning that patients only reported an increase in pain perception when low levels of progesterone and high levels of cortisol coexisted [29]. The result of therapeutic models using testosterone gel for the treatment of fibromyalgia was consistent with the hypothesized role for the hormone, with clinical improvement evidenced in the target population of 11 biological male and female patients [30]. ...
Millions of people are affected by pain-related conditions worldwide. Literature has consistently shown that each individual experiences and perceives pain in a unique manner due to biological, environmental, and cultural factors in which they have been raised. It has been established that biological males and females perceive pain differently and that it may be partially explained by their distinct hormonal profiles since birth, which are only further magnified during puberty. For biological males, high levels of testosterone have shown to increase their pain threshold; and for biological females, estrogen fluctuations have shown to increase pain intensity and perception. However, sex hormones have not been studied in the context of pain treatment or their impact on biochemical pathways involved in pain perception. For this purpose, the transgender community serves as a unique population to investigate the impact of hormone replacement therapy on molecular pathways involved in the perception of pain. The purpose of this review is to explore the biochemistry of hormone replacement in transgender patients who also have other pain-related conditions such as headaches, fibromyalgia, temporomandibular myalgia, and visceral pain.
... In animal models, ablation of estrogen receptors eliminates sex differences in pain entirely (Li et al., 2009). In humans, testosterone therapy successfully relieves fibromyalgia pain (Dubick, Ravin, Michel, & Morrisette, 2015;White et al., 2015). ...
We extend Benenson et al.'s hypothesis from the individual level to the societal level. Because women have highly limited reproductive rates, societies have generally prioritized female survival and regarded males as expendable. We describe various lines of evidence that are consistent with this hypothesis, and we offer additional predictions about differential attitudes toward male versus female endangerment.
... In animal models, ablation of estrogen receptors eliminates sex differences in pain entirely (Li et al., 2009). In humans, testosterone therapy successfully relieves fibromyalgia pain (Dubick, Ravin, Michel, & Morrisette, 2015;White et al., 2015). ...
Extending Campbell's (1999) staying alive theory (SAT) beyond aggression, we reviewed evidence that females are more self-protective than males. Many commentators provided additional supporting data. Sex differences in life-history adaptations, in the optimal relation between survival and reproduction, and in the mechanisms underlying trade-offs involved with self-protection remain important topics with numerous opportunities for improved understanding.
... In animal models, ablation of estrogen receptors eliminates sex differences in pain entirely (Li et al., 2009). In humans, testosterone therapy successfully relieves fibromyalgia pain (Dubick, Ravin, Michel, & Morrisette, 2015;White et al., 2015). ...
The target article presented a plausible argument that females' susceptibility to threats might be self-protection for staying alive, but some evidence requires scrutiny. We need to consider (1) the biases of narrative reviews, (2) subjective life quality, and (3) the shadow side of extreme reactions to threats before concluding that females' threat-based response is a self-protection mechanism that promotes survival.
Objective:
To compare the changes of metabolites between Low-level light therapy (LLLT) and combined oral contraceptive (COC) after treatment of primary dysmenorrhea (PD), and to compare and analyze the biological and biochemical effects of the two treatments by analyzing the differences in metabolite profiles.
Methods:
A multicenter, double-blind, prospective, parallel, randomized controlled study was conducted on 69 women aged 16-35 years old with PD who were randomly divided into COC treatment group or LLLT treatment group. Low-level light therapy with light-emitting diodes (LED) was applied on two acupoints named "Guanyuan" (CV4) and "Qihai" (CV6). After 12 weeks of treatment intervention, blood samples were collected before and after treatment for metabolomic analysis. We used UPLC-MS/MS analysis to compare the differences in metabolite changes between LLLT and COC before and after treatment.
Results:
76 differential metabolites were detected in the LLLT group, and 92 differential metabolites were detected in the COC group, which were up-regulated or down-regulated (p < 0.001). Prostaglandin D2 (PG D2) was down-regulated and biliverdin was up-regulated after LLLT treatment, 4a-Hydroxytetrahydrobiopterin, Prostaglandin D2, 5-Hydroxy-l-tryptophan, Cholic acid were down-regulated and cortisol was up-regulated after COC treatment, and the differences were statistically significant. Cortisol and testosterone glucuronide in LLLT group were significantly lower than those in COC group. The metabolic pathways affected were glycerophospholipid metabolism, linoleic acid metabolism and arachidonic acid metabolism in the LLLT group, and glycerophospholipid metabolism, folate biosynthesis, arachidonic-acid-metabolism, and tryptophan metabolism in the COC group. The differential metabolic pathway were linoleic acid metabolism, steroid hormone biosynthesis, and alpha-Linolenic acid metabolism after the comparison of LLLT with COC.
Conclusion:
LLLT and COC might relieve dysmenorrhea by down-regulating PGD2, and LLLT might also relieve dysmenorrhea by up-regulating biliverdin. The level of cortisol and testosterone glucuronide after LLLT treatment was lower than that after COC treatment, which might lead to the difference in the clinical efficacy of the two treatments for dysmenorrhea.
Chronic pain is a significant health problem associated with disability and reduced quality of life. Current management of chronic pain is inadequate with only modest effects of pharmacological interventions. Thus, there is a need for the generation of analgesics for treating chronic pain. While preclinical and clinical studies demonstrate the analgesic effects of testosterone, clinical use of testosterone is limited by adverse androgenic effects. Selective androgen receptor modulators (SARMs) activate androgen receptors and overcome treatment limitations by minimizing androgenic side effects. Thus, we tested if daily soluble SARMs or a SARM-loaded microparticle formulation alleviated muscle hyperalgesia in a mouse-model of widespread pain (male and female C57BL/6J mice). We tested if the analgesic effects of the SARM-loaded microparticle formulation was mediated through androgen receptors by blocking androgen receptors with flutamide pellets. In vitro and in vivo release kinetics were determined for SARM-loaded microparticles. Safety and toxicity of SARM treatment was determined using serum cardiac and liver toxicity panels, heart histology, and conditioned place preference testing. Subcutaneous daily SARM administration, and 2 injections, I week apart, of SARM-loaded microparticles alleviated muscle hyperalgesia in both sexes and was prevented with flutamide treatment. Sustained release of SARM, from the microparticle formulation, was observed both in vitro and in vivo for 4 weeks. SARM treatment produced no cardiac or liver toxicity and did not produce rewarding behaviors. These studies demonstrate SARM-loaded microparticles alleviate muscle pain, release drug for a sustained period, are safe, and may serve as a potential therapeutic for chronic muscle pain.
Sex/gender is a continuous variable that researchers frequently treat as dichotomous. This practice can mask continuous underlying adaptive traits and yield spurious dichotomous “sex differences.” As such, many sex differences in self-protection may be evolutionary by-products of underlying adaptations rather than adaptations themselves. Binary analysis of continuous sex/gender is ill-considered science that can contribute to inequality and counterproductive public policy.
Resistance training-based exercise is commonly prescribed in the clinic for the treatment of chronic pain. Mechanisms of aerobic exercise for analgesia are frequently studied, while little is known regarding resistance training mechanisms. We developed a resistance training model in mice and hypothesized resistance training would protect against development of muscle pain, mediated through the activation of androgen receptors. Activity induced muscle hyperalgesia was produced by two injections of pH 5.0 stimuli with fatiguing muscle contractions. Resistance training was performed by having mice climb a ladder with attached weights, 3x per week. Resistance training acutely increased blood lactate and prolonged training increased strength measured via forepaw grip strength and 1 repetition maximum, validating the exercise program as a resistance training model. Eight weeks of resistance training prior to induction of the pain model blocked the development of muscle hyperalgesia in both sexes. Resistance training initiated after induction of the pain model reversed muscle hyperalgesia in males only. A single resistance training bout acutely increased testosterone in male but not female mice. Administration of the androgen receptor antagonist flutamide (200mg pellets) throughout the eight-week training program blocked the exercise induced protection against muscle pain in both sexes. However, single administration of flutamide (1, 3, 10mg/kg) in resistance trained animals had no effect on existing exercise induced protection against muscle pain. Therefore, resistance training acutely increases lactate and testosterone and strength overtime. Eight weeks of resistance training prevents development of hyperalgesia through activation of androgen receptors in an animal model of muscle pain.
Fibromyalgia has previously been categorized as primary, secondary, and juvenile fibromyalgia. However, these definitions do not adequately further understanding of the etiopathology of disease nor do they help direct new specific therapies. Herein, we review the previously known categorizations of fibromyalgia. Based on common patient characteristics and previously studied pathophysiologies, we propose new subcategorizations of fibromyalgia that we have self-narrated, including hormonal fibromyalgia, neuroendocrine fibromyalgia, psychologic fibromyalgia, inflammatory fibromyalgia, and lastly neuropathic fibromyalgia. To verify, add to, and fully describe these self-narrated categories of fibromyalgia that we have proposed, future research needs to be done.
Objective:
This position statement aimed to update the evidence-based position statement published by The North American Menopause Society (NAMS) in 2010 regarding recommendations for hormone therapy (HT) for postmenopausal women. This updated position statement further distinguishes the emerging differences in the therapeutic benefit-risk ratio between estrogen therapy (ET) and combined estrogen-progestogen therapy (EPT) at various ages and time intervals since menopause onset.
Methods:
An Advisory Panel of expert clinicians and researchers in the field of women's health was enlisted to review the 2010 NAMS position statement, evaluate new evidence, and reach consensus on recommendations. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees as an official NAMS position statement.
Results:
Current evidence supports the use of HT for perimenopausal and postmenopausal women when the balance of potential benefits and risks is favorable for the individual woman. This position statement reviews the effects of ET and EPT on many aspects of women's health and recognizes the greater safety profile associated with ET.
Conclusions:
Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms and to prevent osteoporosis in women at high risk of fracture. The more favorable benefit-risk ratio for ET allows more flexibility in extending the duration of use compared with EPT, where the earlier appearance of increased breast cancer risk precludes a recommendation for use beyond 3 to 5 years.
Importance
Fibromyalgia is present in as much as 2% to 8% of the population, is characterized by widespread pain, and is often accompanied by fatigue, memory problems, and sleep disturbances.Objective
To review the epidemiology, pathophysiology, diagnosis, and treatment of fibromyalgia.Evidence Review
The medical literature on fibromyalgia was reviewed from 1955 to March 2014 via MEDLINE and the Cochrane Central Registry of Controlled Trials, with an emphasis on meta-analyses and contemporary evidence-based treatment guidelines. Treatment recommendations are based on the most recent evidence-based guidelines from the Canadian Pain Society and graded from 1 to 5 based on the level of available evidence.Findings
Numerous treatments are available for managing fibromyalgia that are supported by high-quality evidence. These include nonpharmacological therapies (education, exercise, cognitive behavioral therapy) and pharmacological therapies (tricyclics, serotonin norepinephrine reuptake inhibitors, and gabapentinoids).Conclusions and Relevance
Fibromyalgia and other “centralized” pain states are much better understood now than ever before. Fibromyalgia may be considered as a discrete diagnosis or as a constellation of symptoms characterized by central nervous system pain amplification with concomitant fatigue, memory problems, and sleep and mood disturbances. Effective treatment for fibromyalgia is now possible.
Objective:
To study the effect of fluoxetine (FL) and amitriptyline (AM), alone and in combination, in patients with fibromyalgia (FM).
Methods:
Nineteen patients with FM completed a randomized, double-blind crossover study, which consisted of 4 6-week trials of FL (20 mg), AM (25 mg), a combination of FL and AM, or placebo. Patients were evaluated on the first and last day of each trial period. Outcome measures included a tender point score, the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI) scale, and visual analog scales (VAS) for global well-being (1 completed by the physician and 1 by the patient), pain, sleep trouble, fatigue, and feeling refreshed upon awakening.
Results:
Both FL and AM were associated with significantly improved scores on the FIQ and on the VAS for pain, global well-being, and sleep disturbances. When combined, the 2 treatments worked better than either medication alone. Similar, but nonsignificant, improvement occurred in the BDI scale, the physician global VAS, and the VAS for fatigue and feeling refreshed upon awakening. Trends were less clear for the tender point score.
Conclusion:
Both FL and AM are effective treatments for FM, and they work better in combination than either medication alone.