Pregabalin for the treatment of fibromyalgia

INTRODUCTION: Fibromyalgia (FM) is the most common cause of chronic widespread body pain in humans. Co-morbidities include sleep disturbance, fatigue, impaired physical functioning, altered mood and negative effects on health-related quality of life. Pregabalin inhibits presynaptic release of pronociceptive neurotransmitters in the CNS; this likely underpins its therapeutic benefit in patients with FM. AREAS COVERED: This review addresses pregabalin pharmacokinetics, efficacy and adverse event (AE) profiles from randomized controlled trials and open-label extension studies in patients with FM. These effects are compared with those of the serotonin norepinephrine reuptake inhibitors, duloxetine and milnacipran that also have FDA approval for the treatment of fibromyalgia. EXPERT OPINION: At the approved dosages, oral pregabalin has at most a moderate therapeutic benefit above placebo with tolerable side-effects, in no more than 50% of patients with FM. Durability of clinically meaningful (≥ 30%) pain relief in pregabalin-responders has been demonstrated for at least 6-months, but longer-term studies are required as most patients have symptoms for decades. Exclusion of patients with common co-morbidities from the pregabalin RCTs in FM raises questions on the generalizability of the RCT findings to the typical patient seen in clinical practice and so additional investigation is required.     

The safety and efficacy of pregabalin for treating subjects with fibromyalgia and moderate or severe baseline widespread pain

Objective To evaluate pregabalin’s efficacy (≤12 weeks) for pain relief and sleep improvement in patients with fibromyalgia (FM) and moderate-to-severe baseline pain.

Research design and methods Data were pooled from five randomized, double-blind, placebo-controlled, phase III clinical trials of pregabalin (300–450 mg/day) for FM treatment. Subjects, aged?≥18 years, had moderate (≥4–<7) or severe (≥7–10) mean baseline pain scores. Analyses included mixed effects repeated measures (MMRM), baseline observation carried forward (for parameters without enough data points for MMRM), or logistic regression.

Clinical trial registration Study number/ClinicalTrials.gov number: A0081056/NCT00645398, A0081077/NCT00230776, A0081100/NCT00333866, A0081208/NCT00830167.

Main outcomes measures Endpoints included mean change in pain and sleep quality scores (Weeks 8 and 12), patient-reported outcomes, and adverse events (AEs).

Results Baseline demographic characteristics were comparable between pregabalin and placebo in both baseline pain severity groups. Mean?±?SD baseline pain severity scores were equivalent between pregabalin and placebo within moderate (5.8?±?0.8) or severe pain (7.9?±?0.7) subgroups. All subjects reported reduced pain and improved sleep quality through Weeks 8 and 12, with larger effects observed with pregabalin over placebo and with baseline severe over moderate pain (all p?<?0.01). Pregabalin was generally well tolerated, AE findings were consistent with previously published trials, and AE profiles were similar between moderate and severe baseline pain subgroups. Limitations of this pooled analysis included differences in individual trial designs (e.g., dosing schedules, racial distribution, exclusion criteria that did not enroll mild severity patients).

Conclusions Pregabalin was efficacious through 12 weeks for reducing pain and improving sleep quality in FM patients with baseline moderate or severe pain, with larger effects in the baseline severe pain subgroup. AEs were consistent with pregabalin’s known safety profile and did not differ between moderate and severe pain subgroups.     

Efficacy and safety of mirogabalin for the treatment of fibromyalgia: results from three 13-week randomized,double-blind,placebo- and active-controlled,parallel-group studies and a 52-week open-label extension study

Objective: To investigate the efficacy and safety of mirogabalin, an α₂δ ligand, in patients with fibromyalgia (FM).

Methods: In three 13-week, multicenter, double-blind, phase 3 studies (studies A, B, and C), patients with FM (n?=?1293, 1270, and 1301, respectively) were randomized (1:1:1:1) to placebo, pregabalin 150?mg twice daily, mirogabalin 15?mg once daily or mirogabalin 15?mg twice daily. The primary endpoint was the change in weekly average daily worst pain score (ADPS) at week 13. Key secondary endpoints included Patient Global Impression of Change and change in the Fibromyalgia Impact Questionnaire total score. Long-term safety of mirogabalin was assessed in a 52-week extension study.

Results: Neither mirogabalin dose demonstrated a significant ADPS reduction from baseline vs. placebo at week 13 in any of the three studies. Pregabalin significantly reduced ADPS from baseline vs. placebo in studies B and C (p?=?.0008 and .0001, respectively). The effect of mirogabalin compared with placebo on key secondary endpoints was variable across the studies. Mirogabalin was well tolerated by most patients in the phase 3 studies; no unexpected adverse events occurring during the 52-week extension study.

Conclusion: While both mirogabalin doses were well tolerated by most patients and showed potential for reducing pain associated with FM, the primary endpoint of significant pain reduction in patients on mirogabalin compared with placebo was not achieved in any of the three randomized controlled studies.

Clinical trial registration: NCT02146430; NCT02187159; NCT02187471; and NCT02234583 (extension study).     

Pregabalin for the treatment of postsurgical pain

Importance of the field: Multimodal postoperative pain management targeted at diminishing harmful outcomes should include pregabalin in cases that need opioid reduction and when the risk of developing chronic neuropathic postsurgical pain is present. Gabapentanoids have grown in importance due to their opioid-sparing effects. They may also contribute to the prevention of chronic postsurgical pain.

Areas covered in this review: We reviewed the literature regarding the use of gabapentanoids and their role in treatment modalities in acute postsurgical pain. Dosing, therapeutic efficacy, side effects, and their role within a multimodal regimen are discussed. Particular emphasis is placed on their ability to provide an opioid-sparing effect, as well as on their potential for inhibiting chronic neuropathic pain. A Pubmed search of pregabalin, gabapentin, acute pain, multimodal analgesia, chronic postsurgical pain, and neuropathic pain between 2000 and 2010 was done. Relevant articles – including randomized controlled trials, retrospective trials, case series, case reports, and review articles – were filtered to include those that relate to postsurgical pain.

What the reader will gain: Readers will gain an increased appreciation of the role of pregabalin in postsurgical pain in patients at risk of developing chronic pain.

Take home message: Pregabalin is a safe and effective medication that may decrease perioperative opioid use in patients with more acute neuropathic pain than acute inflammatory pain. When surgery involves more neuropathic-type acute pain there is growing evidence that pregabalin may decrease the incidence of chronic pain.     

The efficacy of pregabalin in patients with moderate and severe pain due to diabetic peripheral neuropathy

Objective To compare the therapeutic response to pregabalin in patients with moderate or severe painful diabetic peripheral neuropathy (pDPN).

Research design and methods Data were pooled from 11 placebo-controlled trials to evaluate the efficacy of pregabalin flexible or fixed dose (150, 300 or 600?mg/day) in pDPN patients with mean baseline pain scores of ≥4 to <7 (moderate) or ≥7 to ≤10 (severe). Last observation carried forward imputation was used.

Study number/ClinicalTrials.gov identifier 1008-014/-, 1008-029/-, 1008-040/-, 1008-131/-, 1008-149/-, 1008-000-155/-, A0081030/NCT00156078, A0081060/NCT00159679, A0081071/NCT00143156, A0081081/NCT00301223, A0081163/NCT00553475.

Main outcome measures Pregabalin-mediated change in pain, pain-related sleep interference (PRSI) and patient global impression of change (PGIC) were compared versus placebo and between moderate and severe pain cohorts. Adverse events (AEs) were reported.

Results At baseline, 1816 patients had moderate pain (pregabalin, n?=?1189) and 1119 patients had severe pain (pregabalin, n?=?720). Pregabalin significantly reduced pain scores at endpoint compared with placebo when patients of all pain levels were combined (all doses; p?<?0.05). In the moderate and severe pain cohorts, pregabalin treatment (300, 600?mg/day or flexible) significantly reduced mean pain scores at endpoint compared with placebo (p?<?0.01). Pain reduction was greatest in patients with severe baseline pain compared with moderate baseline pain (pregabalin 300, 600?mg/day or flexible; p?<?0.0001). Pregabalin improved PRSI and PGIC in the moderate and severe cohorts compared with placebo. The greatest improvement in PRSI also occurred in the severe cohort. Treatment-emergent AEs, most commonly dizziness, somnolence and peripheral edema, occurred more frequently in patients treated with pregabalin compared with placebo.

Conclusions Pregabalin was effective in pDPN patients with both moderate and severe baseline pain. Patients with severe pain exhibited greater improvements in pain and PRSI than patients with moderate pain. Pain severity may, in part, predict therapeutic response to pregabalin.     

Treatment response to pregabalin in fibromyalgia pain: effect of patient baseline characteristics

Objective: The objective of this study was to evaluate the effect of patients' characteristics at baseline on the magnitude of pain response to pregabalin in patients with fibromyalgia.

Methods: Data from four randomized, multicenter, placebo-controlled clinical studies of pregabalin in patients with fibromyalgia were used for the analysis. Approved doses (300 and 450 mg/day) were pooled to enhance the sensitivity of the interaction tests. A centered covariate interaction model was used to assess the treatment effects; a noncentered model was used for estimated mean pain changes and least square means across different levels of baseline covariates. The interaction was considered significant if p < 0.10.

Results: In total, 2061 patients (median age, 49 years; median pain score, 7.0; median duration of fibromyalgia, 83 months) were included in this analysis. No significant interaction was observed between treatment and anxiety, depression, or duration of fibromyalgia. Significant treatment by baseline mean pain (p = 0.037), treatment by baseline sleep score (p = 0.071), and treatment by age (p = 0.051) interactions were observed.

Conclusion: The magnitude of response to pregabalin in terms of changes in pain may depend on age, pain, and sleep levels at baseline in patients with fibromyalgia.     

An evidence-based review of pregabalin for the treatment of fibromyalgia

Objectives: Pregabalin, an α2-δ agonist, is approved for the treatment of fibromyalgia (FM) in the United States, Japan, and 37 other countries. The purpose of this article was to provide an in-depth, evidence-based summary of pregabalin for FM as demonstrated in randomized, placebo-controlled clinical studies, including open-label extensions, meta-analyses, combination studies and post-hoc analyses of clinical study data.

Methods: PubMed was searched using the term “pregabalin AND fibromyalgia” and the Cochrane Library with the term “pregabalin”. Both searches were conducted on 2 March 2017 with no other date limits set.

Results: Eleven randomized, double-blind, placebo-controlled clinical studies were identified including parallel group, two-way crossover and randomized withdrawal designs. One was a neuroimaging study. Five open-label extensions were also identified. Evidence of efficacy was demonstrated across the studies identified with significant and clinically relevant improvements in pain, sleep quality and patient status. The safety and tolerability profile of pregabalin is consistent across all the studies identified, including in adolescents, with dizziness and somnolence the most common adverse events reported. These efficacy and safety data are supported by meta-analyses (13 studies). Pregabalin in combination with other pharmacotherapies (7 studies) is also efficacious. Post-hoc analyses have demonstrated the onset of pregabalin efficacy as early as 1–2 days after starting treatment, examined the effect of pregabalin on other aspects of sleep beyond quality, and shown it is effective irrespective of the presence of a wide variety of patient demographic and clinical characteristics.

Conclusions: Pregabalin is a treatment option for FM; its clinical utility has been comprehensively demonstrated.     

Medical conditions in fibromyalgia patients and their relationship to pregabalin efficacy: pooled analysis of Phase III clinical trials

Objective: Patients with fibromyalgia demonstrate high rates of comorbid somatic and psychiatric disorders. The current post hoc study analyzed the prevalence of comorbid conditions and their relationship to pregabalin efficacy in patients with fibromyalgia pooled from four Phase III clinical trials.

Methods: Patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria, randomized to placebo or 300, 450, or 600 mg/day pregabalin, and with ≥ 1 postbaseline pain score were included. The frequency of comorbid conditions was obtained from patient-reported, voluntary medical histories. Patients were categorized based on the presence of a medical condition (e.g., irritable bowel syndrome) or a group of medical conditions (e.g., neurological disorders). Two efficacy variables were examined within each comorbid category: endpoint changes from baseline in weekly mean pain diary scores (11-point numeric rating scale) and Patient Global Impression of Change.

Results: A large proportion of patients exhibited concomitant headache, immunological (allergy), gastroesophageal, and/or psychiatric disorders. The efficacy analyses performed on these subgroups of patients, amongst others, showed – with few exceptions – consistent pain reductions of similar magnitude with pregabalin.

Conclusion: Comorbid conditions are common among patients with fibromyalgia and their presence is not associated with altered pregabalin efficacy.     

Delta‐9-THC based monotherapy in fibromyalgia patients on experimentally induced pain,axon reflex flare,and pain relief

ABSTRACT

Objective: Fibromyalgia (FM) is a chronic pain syndrome characterized by a distinct mechanical hyperalgesia and chronic pain. Recently, cannabinoids have been demonstrated as providing anti-nociceptive and anti-hyperalgesic effects in animal and human studies. Here, we explored in nine FM patients the efficacy of orally administered delta-9-tetrahydrocannabinol (THC) on electrically induced pain, axon reflex flare, and psychometric variables.

Research design and methods: Patients received a daily dose of 2.5–15?mg of delta‐9-THC, with a weekly increase of 2.5?mg, as long as no side effects were reported. Psychometric variables were assessed each week by means of the West Haven-Yale Multidimensional Pain Inventory (MPI), Pittsburgh Sleep Quality Index (PSQI), Medical outcome survey-short form (MOS SF‐36), the Pain Disability Index (PDI), and the Fibromyalgia Impact Questionnaire (FIQ). In addition, patients recorded daily, in a diary, their overall pain intensity on a numeric scale. Each week, pain and axon reflex flare was evoked experimentally by administration of high intensity constant current pulses (1?Hz, pulse width 0.2?ms, current increase stepwise from 2.5–12.5?mA every 3 minutes) delivered via small surface electrodes, attached to the volar forearm skin.

Main outcome measures: Daily pain recordings by the patient, experimentally induced pain, and axon reflex flare recorded by a laser Doppler scanner.

Results: Five of nine FM patients withdrew during the study due to adverse side effects. Delta‐9-THC had no effect on the axon reflex flare, whereas electrically induced pain was significantly attenuated after doses of 10–15?mg delta‐9-THC (?p < 0.05). Daily-recorded pain of the FM patients was significantly reduced (?p < 0.01).

Conclusions: This pilot study demonstrated that a generalized statement that delta‐9-THC is an analgetic drug cannot be made. However, a sub-population of FM patients reported significant benefit from the delta‐9-THC monotherapy. The unaffected electrically induced axon reflex flare, but decreased pain perception, suggests a central mode of action of the cannabinoid.     

Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia

Objectives: Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment.

Methods: In this study, the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10?mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals’ locomotor activity was also studied.

Results: In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (p?p?p?p?Discussion: In passive avoidance task, pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze, pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain).     

Sodium oxybate for the treatment of fibromyalgia

Introduction: Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid that is synthesized within the CNS, mostly from its parent compound gamma amino butyric acid (GABA). GHB acts as a neuromodulator/neurotransmitter to affect neuronal activity of other neurotransmitters and so, stimulate the release of growth hormone. Its sodium salt (sodium oxybate: SXB) was approved by the Food and Drug Administration (FDA) for the treatment of narcolepsy. SXB has shown to improve disrupted sleep and increase NR3 (slow-wave restorative) sleep in patients with narcolepsy. It is rapidly absorbed and has a plasma half-life of 30 – 60 min, necessitating twice-nightly dosing. Most of the observed effects of SXB result from binding to GABA-B receptors.

Areas covered: Several randomized, controlled trials demonstrated significantly improved fibromyalgia (FM) symptoms with SXB. As seen in narcolepsy trials, SXB improved sleep of FM patients, increased slow-wave sleep duration as well as delta power, and reduced frequent night-time awakenings. Furthermore, FM pain and fatigue was consistently reduced with nightly SXB over time. Commonly reported adverse events included headache, nausea, dizziness and somnolence. Despite its proven efficacy, SXB did not receive FDA approval for the management of FM in 2010, mostly because of concerns about abuse.

Expert opinion: Insomnia, fatigue and pain are important clinical FM symptoms that showed moderate improvements with SXB in several large, well-designed clinical trials. Because of the limited efficacy of currently available FM drugs additional treatment options are needed. In particular, drugs like SXB – which belong to a different drug class than other Food and Drug Administration (FDA)-approved FM medications such as pregabalin, duloxetine and milnacipran – would provide a much-needed addition to presently available treatment options. However, the FDA has set the bar high for future SXB re-submissions, with requirements of superior efficacy and improved risk mitigation strategies. At this time, no future FDA submission of SXB for the fibromyalgia indication is planned.     

Prediction of therapeutic response to pregabalin in subjects with neuropathic pain

Objective: To evaluate four models based on potential predictors for achieving a response to pregabalin treatment for neuropathic pain (NeP).

Methods: In total, 46 pain studies were screened, of which 27 NeP studies met the criteria for inclusion in this analysis. Data were pooled from these 27 placebo-controlled randomized trials to assess if baseline characteristics (including mean pain and pain-related sleep interference [PRSI] scores), early clinical response during weeks 1–3 of treatment (change from baseline in pain and PRSI scores), and presence of treatment-emergent adverse events (AEs) were predictive of therapeutic response. Therapeutic response was defined as a ≥30% reduction from baseline in either pain and/or PRSI scores at week 5 with supplemental analyses to predict pain outcomes at weeks 8 and 12. Predictors of Patient Global Impression of Change (PGIC) were also evaluated. Four models were assessed: Random Forest, Logistic Regression, Naïve Bayes, and Partial Least Squares.

Results: The number of pregabalin-treated subjects in the training/test datasets, respectively, were 2818/1407 (30% pain analysis), 2812/1405 (30% sleep analysis), and 2693/1345 (PGIC analysis). All four models demonstrated consistent results, and the most important predictors of treatment outcomes at week 5 and pain outcomes at weeks 8 and 12 were the reduction in pain score and sleep score in the first 1–3 weeks. The presence or absence of the most common AEs in the first 1–3 weeks was not correlated with any treatment outcome.

Conclusions: Subjects with an early response to pregabalin are more likely to experience an end-of-treatment response.     

Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13‐week,randomized trial

ABSTRACT

Objective: This trial evaluated the efficacy and safety of pregabalin dosed twice daily (BID) for relief of neuro-pathic pain associated with postherpetic neuralgia (PHN).

Research design and methods: The 13‐week, double-blind, placebo-controlled study randomized 370 patients with PHN to pregabalin (150, 300, or 600?mg/day BID) or placebo.

Main outcome measures: Primary efficacy measure was endpoint mean pain score from daily pain diaries. Secondary efficacy measures included endpoint mean sleep-interference score from daily sleep diaries and Patient Global Impression of Change (PGIC). Safety evaluations included adverse events (AEs), physical and neurologic examinations, 12-lead ECG, vital signs, and laboratory testing.

Results: Pregabalin provided significant, dose-proportional pain relief at endpoint: difference from placebo in mean pain score, 150?mg/day, –0.88, p = 0.0077; 300?mg/day, –1.07, p = 0.0016; 600?mg/day, –1.79, p = 0.0003. Weekly mean pain scores significantly improved as early as week 1. Sleep interference in all pregabalin groups was also significantly improved at endpoint, compared with placebo (?p < 0.001), beginning at week 1 (?p < 0.01). At study termination, patients in the 150 (p = 0.02) and 600?mg/day (p = 0.003) groups were more likely to report global improvement than were those in the placebo group.

Most AEs were mild or moderate. Among pregabalin-treated patients, 13.5% withdrew due to AEs, most commonly for dizziness (16 patients, 5.8%), somnolence (8, 2.9%), or ataxia (7, 2.5%).

Conclusions: Pregabalin, dosed BID, reduced neuropathic pain associated with PHN and was well tolerated. It also reduced the extent to which pain interfered with sleep. Pregabalin's effects were seen as early as week 1 and were sustained throughout the 13‐week study.     

Efficacy and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin in post-herpetic neuralgia and diabetic polyneuropathy

ABSTRACT

Objective: Neuropathic pain is often difficult to treat due to a complex pathophysiology. This study evaluated the efficacy, tolerability and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin for neuropathic pain in patients with post-herpetic neuralgia (PHN) or painful diabetic polyneuropathy (DPN).

Methods: Patients completing 4-week monotherapy with 5% lidocaine medicated plaster or pregabalin were enrolled in an 8-week combination phase. Patients with adequate response to monotherapy (recalled average pain intensity of 4 or less on 11-point numeric rating scale in the previous 3 days [NRS-3 score]) continued their previous therapy, whereas those with insufficient response received combination therapy. Efficacy endpoints included change in NRS-3 from combination phase baseline, Patient and Clinical Global Impression of Change (PGIC/CGIC), and patient's satisfaction with treatment. Safety evaluation included adverse events (AEs), drug-related AEs (DRAEs), and withdrawal due to AEs.

Clinical trial registration: EudraCT No. 2006-003132-29.

Results: Of 229 patients in the per-protocol set (PPS: 68 PHN and 161 DPN), 71 received 5% lidocaine medicated plaster monotherapy, 57 had pregabalin added to 5% lidocaine medicated plaster, 57 pregabalin monotherapy and 44 received 5% lidocaine medicated plaster in addition to continued pregabalin treatment. There were no meaningful differences in demographic data between the treatment groups. Patients continuing on monotherapy demonstrated additional decreases in NRS-3 scores. Patients receiving combination therapy achieved clinically relevant reduction in NRS-3 values in addition to improvement achieved during the 4 weeks of monotherapy. Improvement was similar between the two combination therapy groups. Considerable improvements in patients’ treatment satisfaction were reported. Incidences of AEs were in line with previous reports for the two treatments and combination therapy was generally well tolerated.

Conclusions: In patients with PHN and painful DPN failing to respond to monotherapy, combination therapy with 5% lidocaine medicated plaster and pregabalin provides additional clinically relevant pain relief and is safe and well-tolerated.     

The effect of pregabalin on pain-related sleep interference in diabetic peripheral neuropathy or postherpetic neuralgia: a review of nine clinical trials

Abstract

Objective:

Postherpetic neuralgia and painful diabetic peripheral neuropathy are common chronic neuropathic pain conditions associated with sleep disturbances. Pregabalin is indicated in the treatment of neuropathic pain. The objective of this review is to summarize the efficacy and safety of pregabalin in painful diabetic peripheral neuropathy and postherpetic neuralgia and the effect of pregabalin on sleep interference in these patients.     

Testosterone undecanoate in the treatment of male hypogonadism

Importance of the field: Testosterone undecanoate (TU) represents an exciting new testosterone replacement therapy for hypogonadal men due to its convenient dosing schedule and favorable pharmacokinetic and safety profiles.

Areas covered in this review: Clinical, pharmacokinetic and safety characteristics of TU will be reviewed. The characteristics of currently approved testosterone therapies will be reviewed and compared with those of TU in order to determine which therapy most appropriately meets the clinical objective of properly matching a patient with a therapy that is best able to deliver physiological levels of testosterone for prolonged periods of time, while at the same time being safe, effective, inexpensive, simple to use, and with few side effects.

What the reader will gain: TU represents the first long-acting injectable with an excellent safety profile that can be administered only four times annually to produce stable levels of testosterone. Long-term studies have validated the clinical efficacy of TU in maintaining therapeutic levels of testosterone. Patient preference for the convenient dosing schedule might also lead to better compliance and therapeutic benefit. No serious side effects have been noted with the use of TU, including long-term data on patients treated with TU over 8 years.

Take home message: TU is both a desirable and safe option for the treatment of hypogonadal men. Patients will benefit from the stable testosterone levels and fewer required injections, while achieving the desired benefits of androgen replacement.     

Autoimmunity in intervertebral disc herniation: from bench to bedside

Introduction: The cause of low back pain and the pathophysiology of lumbar pain and sciatica have recently been reconsidered basing on current knowledge on cellular and molecular mediators of inflammation. Several cytokines have been considered as potential therapeutic targets to contrast sciatica in patients with disc herniation, and supportive studies suggest a leading role of TNF-α in this contest: therefore, clinical trials have tested TNF-α inhibitors in the clinical setting of the patient with radicular pain secondary to an herniated disc.

Areas covered: The current review deals with the autoimmune theory of disc herniation and its role in determining radiculopathy and neuropathic pain. It also reports the recent evidences that led to the introduction of anti-TNF-α drugs into the clinical setting as a biological therapy for radiculopathy and disc herniation.

Expert opinion: Targeting the TNF-α pathway has demonstrated controversial effects in the tested study population and available results only report a short-term follow-up. More confirmatory studies in terms of long-term clinical results, complications, more effective route of administration and cost-effective analysis are required to establish the real role of this biological therapy in the treatment of patients with disc herniation and neuropathy.     

The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets?

Introduction: Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are characterized by persistent pain and fatigue. It is hypothesized that reactive oxygen species (ROS), caused by oxidative and nitrosative stress, by inhibiting mitochondrial function can be involved in muscle pain and central sensitization as typically seen in these patients.

Areas covered: The current evidence regarding oxidative and nitrosative stress and mitochondrial dysfunction in CFS and FM is presented in relation to chronic widespread pain. Mitochondrial dysfunction has been shown in leukocytes of CFS patients and in muscle cells of FM patients, which could explain the muscle pain. Additionally, if mitochondrial dysfunction is also present in central neural cells, this could result in lowered ATP pools in neural cells, leading to generalized hypersensitivity and chronic widespread pain.

Expert opinion: Increased ROS in CFS and FM, resulting in impaired mitochondrial function and reduced ATP in muscle and neural cells, might lead to chronic widespread pain in these patients. Therefore, targeting increased ROS by antioxidants and targeting the mitochondrial biogenesis could offer a solution for the chronic pain in these patients. The role of exercise therapy in restoring mitochondrial dysfunction remains to be explored, and provides important avenues for future research in this area.     

New drugs or alternative therapy to blurring the symptoms of fibromyalgia—a patent review

Introduction: Fibromyalgia (FM) is a musculoskeletal condition characterized by chronic widespread pain, tenderness and often accompanied by other comorbid conditions such as depression, anxiety, chronic fatigue, among others. Now, we aimed to survey the recent patents describing new drugs or alternative therapy for FM.

Areas covered: This review covers the therapeutic patents published between 2010 and 2017 from specialized search databases (WIPO, DERWENT, INPI, ESPANET and USPTO) that report the discovery of new drugs or pharmacologic alternative for the treatment of FM.

Expert opinion: New therapeutic substances have been proposed in the last seven years. At least as it has been found in our survey, most are still in the pre-clinical phase of the study, and its clinical applicability is unclear. However, other therapeutic approaches were found in patents such as well-established drugs in the market in combination or drug repositioning that combines the ‘new analgesic’ effects with the old side effects. Hence, it is a safe approach for pharmaceutical market, but poorer to patients who need a radical innovation. So, there is the emerging need for further studies on the safety and efficacy of such therapeutic measures and the search for improvement of side effects, as well as the development of new drugs that are unorthodox for different FM symptoms.