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Lancet (London, England) Aug 2022Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial.
BACKGROUND
Diabetic peripheral neuropathic pain (DPNP) is common and often distressing. Most guidelines recommend amitriptyline, duloxetine, pregabalin, or gabapentin as initial analgesic treatment for DPNP, but there is little comparative evidence on which one is best or whether they should be combined. We aimed to assess the efficacy and tolerability of different combinations of first-line drugs for treatment of DPNP.
METHODS
OPTION-DM was a multicentre, randomised, double-blind, crossover trial in patients with DPNP with mean daily pain numerical rating scale (NRS) of 4 or higher (scale is 0-10) from 13 UK centres. Participants were randomly assigned (1:1:1:1:1:1), with a predetermined randomisation schedule stratified by site using permuted blocks of size six or 12, to receive one of six ordered sequences of the three treatment pathways: amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P), each pathway lasting 16 weeks. Monotherapy was given for 6 weeks and was supplemented with the combination medication if there was suboptimal pain relief (NRS >3), reflecting current clinical practice. Both treatments were titrated towards maximum tolerated dose (75 mg per day for amitriptyline, 120 mg per day for duloxetine, and 600 mg per day for pregabalin). The primary outcome was the difference in 7-day average daily pain during the final week of each pathway. This trial is registered with ISRCTN, ISRCTN17545443.
FINDINGS
Between Nov 14, 2017, and July 29, 2019, 252 patients were screened, 140 patients were randomly assigned, and 130 started a treatment pathway (with 84 completing at least two pathways) and were analysed for the primary outcome. The 7-day average NRS scores at week 16 decreased from a mean 6·6 (SD 1·5) at baseline to 3·3 (1·8) at week 16 in all three pathways. The mean difference was -0·1 (98·3% CI -0·5 to 0·3) for D-P versus A-P, -0·1 (-0·5 to 0·3) for P-A versus A-P, and 0·0 (-0·4 to 0·4) for P-A versus D-P, and thus not significant. Mean NRS reduction in patients on combination therapy was greater than in those who remained on monotherapy (1·0 [SD 1·3] vs 0·2 [1·5]). Adverse events were predictable for the monotherapies: we observed a significant increase in dizziness in the P-A pathway, nausea in the D-P pathway, and dry mouth in the A-P pathway.
INTERPRETATION
To our knowledge, this was the largest and longest ever, head-to-head, crossover neuropathic pain trial. We showed that all three treatment pathways and monotherapies had similar analgesic efficacy. Combination treatment was well tolerated and led to improved pain relief in patients with suboptimal pain control with a monotherapy.
FUNDING
National Institute for Health Research (NIHR) Health Technology Assessment programme.
Topics: Amitriptyline; Analgesics; Cross-Over Studies; Diabetes Mellitus; Diabetic Neuropathies; Double-Blind Method; Duloxetine Hydrochloride; Humans; Neuralgia; Pregabalin; Treatment Outcome; gamma-Aminobutyric Acid
PubMed: 36007534
DOI: 10.1016/S0140-6736(22)01472-6 -
Annals of the Rheumatic Diseases Feb 2017The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most... (Review)
Review
OBJECTIVE
The original European League Against Rheumatism recommendations for managing fibromyalgia assessed evidence up to 2005. The paucity of studies meant that most recommendations were 'expert opinion'.
METHODS
A multidisciplinary group from 12 countries assessed evidence with a focus on systematic reviews and meta-analyses concerned with pharmacological/non-pharmacological management for fibromyalgia. A review, in May 2015, identified eligible publications and key outcomes assessed were pain, fatigue, sleep and daily functioning. The Grading of Recommendations Assessment, Development and Evaluation system was used for making recommendations.
RESULTS
2979 titles were identified: from these 275 full papers were selected for review and 107 reviews (and/or meta-analyses) evaluated as eligible. Based on meta-analyses, the only 'strong for' therapy-based recommendation in the guidelines was exercise. Based on expert opinion, a graduated approach, the following four main stages are suggested underpinned by shared decision-making with patients. Initial management should involve patient education and focus on non-pharmacological therapies. In case of non-response, further therapies (all of which were evaluated as 'weak for' based on meta-analyses) should be tailored to the specific needs of the individual and may involve psychological therapies (for mood disorders and unhelpful coping strategies), pharmacotherapy (for severe pain or sleep disturbance) and/or a multimodal rehabilitation programme (for severe disability).
CONCLUSIONS
These recommendations are underpinned by high-quality reviews and meta-analyses. The size of effect for most treatments is relatively modest. We propose research priorities clarifying who will benefit from specific interventions, their effect in combination and organisation of healthcare systems to optimise outcome.
Topics: Activities of Daily Living; Acupuncture Therapy; Amitriptyline; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Antidepressive Agents, Tricyclic; Biofeedback, Psychology; Capsaicin; Cognitive Behavioral Therapy; Europe; Evidence-Based Medicine; Exercise Therapy; Fatigue; Fibromyalgia; Human Growth Hormone; Humans; Hydrotherapy; Hypnosis; Manipulation, Chiropractic; Massage; Mind-Body Therapies; Mindfulness; Monoamine Oxidase Inhibitors; Pain; Practice Guidelines as Topic; S-Adenosylmethionine; Sensory System Agents; Selective Serotonin Reuptake Inhibitors; Serotonin and Noradrenaline Reuptake Inhibitors; Sleep; Societies, Medical; Sodium Oxybate; Treatment Outcome
PubMed: 27377815
DOI: 10.1136/annrheumdis-2016-209724 -
The Cochrane Database of Systematic... Mar 2022Posttraumatic stress disorder (PTSD) is a prevalent and disabling disorder. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed... (Review)
Review
BACKGROUND
Posttraumatic stress disorder (PTSD) is a prevalent and disabling disorder. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed to a growing interest in the use of medication in its treatment.
OBJECTIVES
To assess the effects of medication for reducing PTSD symptoms in adults with PTSD.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 11, November 2020); MEDLINE (1946-), Embase (1974-), PsycINFO (1967-) and PTSDPubs (all available years) either directly or via the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR). We also searched international trial registers. The date of the latest search was 13 November 2020.
SELECTION CRITERIA
All randomised controlled trials (RCTs) of pharmacotherapy for adults with PTSD.
DATA COLLECTION AND ANALYSIS
Three review authors (TW, JI, and NP) independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. We contacted investigators to obtain missing data. We stratified summary statistics by medication class, and by medication agent for all medications. We calculated dichotomous and continuous measures using a random-effects model, and assessed heterogeneity.
MAIN RESULTS
We include 66 RCTs in the review (range: 13 days to 28 weeks; 7442 participants; age range 18 to 85 years) and 54 in the meta-analysis. For the primary outcome of treatment response, we found evidence of beneficial effect for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.59 to 0.74; 8 studies, 1078 participants), which improved PTSD symptoms in 58% of SSRI participants compared with 35% of placebo participants, based on moderate-certainty evidence. For this outcome we also found evidence of beneficial effect for the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine: (RR 0.45, 95% CI 0.22 to 0.94; 1 study, 26 participants) in 65% of people on mirtazapine compared with 22% of placebo participants, and for the tricyclic antidepressant (TCA) amitriptyline (RR 0.60, 95% CI 0.38 to 0.96; 1 study, 40 participants) in 50% of amitriptyline participants compared with 17% of placebo participants, which improved PTSD symptoms. These outcomes are based on low-certainty evidence. There was however no evidence of beneficial effect for the number of participants who improved with the antipsychotics (RR 0.51, 95% CI 0.16 to 1.67; 2 studies, 43 participants) compared to placebo, based on very low-certainty evidence. For the outcome of treatment withdrawal, we found evidence of a harm for the individual SSRI agents compared with placebo (RR 1.41, 95% CI 1.07 to 1.87; 14 studies, 2399 participants). Withdrawals were also higher for the separate SSRI paroxetine group compared to the placebo group (RR 1.55, 95% CI 1.05 to 2.29; 5 studies, 1101 participants). Nonetheless, the absolute proportion of individuals dropping out from treatment due to adverse events in the SSRI groups was low (9%), based on moderate-certainty evidence. For the rest of the medications compared to placebo, we did not find evidence of harm for individuals dropping out from treatment due to adverse events.
AUTHORS' CONCLUSIONS
The findings of this review support the conclusion that SSRIs improve PTSD symptoms; they are first-line agents for the pharmacotherapy of PTSD, based on moderate-certainty evidence. The NaSSA mirtazapine and the TCA amitriptyline may also improve PTSD symptoms, but this is based on low-certainty evidence. In addition, we found no evidence of benefit for the number of participants who improved following treatment with the antipsychotic group compared to placebo, based on very low-certainty evidence. There remain important gaps in the evidence base, and a continued need for more effective agents in the management of PTSD.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amitriptyline; Antidepressive Agents; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Humans; Middle Aged; Mirtazapine; Paroxetine; Selective Serotonin Reuptake Inhibitors; Stress Disorders, Post-Traumatic; Young Adult
PubMed: 35234292
DOI: 10.1002/14651858.CD002795.pub3 -
Ideggyogyaszati Szemle Jan 2019Tension type headache, the most common type of primary headaches, affects approximately 80% of the population. Mainly because of its high prevalence, the socio-economic... (Review)
Review
Tension type headache, the most common type of primary headaches, affects approximately 80% of the population. Mainly because of its high prevalence, the socio-economic consequences of tension type headache are significant. The pain in tension type headache is usually bilateral, mild to moderate, is of a pressing or tightening quality, and is not accompanied by other symptoms. Patients with frequent or daily occurrence of tension type headache may experience significant distress because of the condition. The two main therapeutic avenues of tension type headache are acute and prophylactic treatment. Simple or combined analgesics are the mainstay of acute treatment. Prophylactic treatment is needed in case of attacks that are frequent and/or difficult to treat. The first drugs of choice as preventatives of tension type headache are tricyclic antidepressants, with a special focus on amitriptyline, the efficacy of which having been documented in multiple double-blind, placebo-controlled studies. Among other antidepressants, the efficacy of mirtazapine and venlafaxine has been documented. There is weaker evidence about the efficacy of gabapentine, topiramate, and tizanidin. Non-pharmacological prophylactic methods of tension type headache with a documented efficacy include certain types of psychotherapy and acupuncture.
Topics: Amitriptyline; Antidepressive Agents, Tricyclic; Humans; Tension-Type Headache
PubMed: 30785242
DOI: 10.18071/isz.72.0013 -
Journal of Midwifery & Women's Health Jan 2023Vulvodynia affects 7% of American women, yet clinicians often lack awareness of its presentation. It is underdiagnosed and often misdiagnosed as vaginitis. The etiology... (Review)
Review
Vulvodynia affects 7% of American women, yet clinicians often lack awareness of its presentation. It is underdiagnosed and often misdiagnosed as vaginitis. The etiology of vulvodynia remains unknown, making it difficult to identify or develop effective treatment methods. The purpose of this article is to (1) review the presentation and evaluation of vulvodynia, (2) review the research on vulvodynia treatments, and (3) aid the clinician in the selection of vulvodynia treatment methods. The level of evidence to support vulvodynia treatment varies from case series to randomized controlled trials (RCTs). Oral desipramine with 5% lidocaine cream, intravaginal diazepam tablets with intravaginal transcutaneous electric nerve stimulation (TENS), botulinum toxin type A 50 units, enoxaparin sodium subcutaneous injections, intravaginal TENS (as a single therapy), multimodal physical therapy, overnight 5% lidocaine ointment, and acupuncture had the highest level of evidence with at least one RCT or comparative effectiveness trial. Pre to posttest reduction in vulvar pain and/or dyspareunia in non-RCT studies included studies of gabapentin cream, amitriptyline cream, amitriptyline with baclofen cream, up to 6 weeks' oral itraconazole therapy, multimodal physical therapy, vaginal dilators, electromyography biofeedback, hypnotherapy, cognitive behavioral therapy, cold knife vestibulectomy, and laser therapy. There is a lack of rigorous RCTs with large sample sizes for the treatment of vulvodynia, rendering it difficult to determine efficacy of most treatment methods. Clinicians will be guided in the selection of best treatments for vulvodynia that have the highest level of evidence and are least invasive.
Topics: Female; Humans; Vulvodynia; Amitriptyline; Treatment Outcome; Lidocaine; Transcutaneous Electric Nerve Stimulation
PubMed: 36533637
DOI: 10.1111/jmwh.13456 -
Molecular Psychiatry Jan 2023A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to... (Meta-Analysis)
Meta-Analysis
A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to treat adults with major depressive disorder (MDD) in the maintenance phase. This study searched the PubMed, Cochrane Library, and Embase databases and included only double-blind, randomized, placebo-controlled trials with an enrichment design: patients were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or placebo. The outcomes were the 6-month relapse rate (primary outcome, efficacy), all-cause discontinuation (acceptability), discontinuation due to adverse events (tolerability), and the incidence of individual adverse events. The risk ratio with a 95% credible interval was calculated. The meta-analysis comprised 34 studies (n = 9384, mean age = 43.80 years, and %females = 68.10%) on 20 antidepressants (agomelatine, amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, vilazodone, and vortioxetine) and a placebo. In terms of the 6-month relapse rate, amitriptyline, citalopram, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, and vortioxetine outperformed placebo. Compared to placebo, desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had lower all-cause discontinuation; however, sertraline had a higher discontinuation rate due to adverse events. Compared to placebo, venlafaxine was associated with a lower incidence of dizziness, while desvenlafaxine, sertraline, and vortioxetine were associated with a higher incidence of nausea/vomiting. In conclusion, desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had reasonable efficacy, acceptability, and tolerability in the treatment of adults with stable MDD.
Topics: Female; Humans; Adult; Depressive Disorder, Major; Duloxetine Hydrochloride; Sertraline; Citalopram; Venlafaxine Hydrochloride; Vortioxetine; Fluoxetine; Paroxetine; Mirtazapine; Amitriptyline; Desvenlafaxine Succinate; Fluvoxamine; Reboxetine; Network Meta-Analysis; Antidepressive Agents; Randomized Controlled Trials as Topic
PubMed: 36253442
DOI: 10.1038/s41380-022-01824-z -
Neurologia Oct 2022Phantom limb pain (PLP) is a type of neuropathic pain that affects the territory of an amputated limb or other surgically removed body parts. Between 60% and 90% of... (Review)
Review
INTRODUCTION
Phantom limb pain (PLP) is a type of neuropathic pain that affects the territory of an amputated limb or other surgically removed body parts. Between 60% and 90% of amputees suffer from PLP during follow-up. There are a range of therapeutic options for PLP, both pharmacological (gabapentin, amitriptyline, tricyclic antidepressants, etc) and non-pharmacological (transcutaneous electrical nerve stimulation, hypnosis, acupuncture, etc). A widely accepted hypothesis considers PLP to be the consequence of postamputation cortical reorganisation. New treatment approaches, such as mirror therapy (MT), have been developed as a result of Ramachandran's groundbreaking research in the 1990s. This review analyses the current evidence on the efficacy of MT for treating PLP.
DEVELOPMENT
We performed a literature review of publications registered from 2012 to 2017 on the CINAHL, Cochrane, Scopus, and PubMed (including Medline) databases using the descriptors "phantom limb" and "mirror therapy." We identified 115 publications addressing MT in PLP. Of these, 17 (15%) contributed useful information for pooled analysis.
CONCLUSIONS
MT seems to be effective in relieving PLP, reducing the intensity and duration of daily pain episodes. It is a valid, simple, and inexpensive treatment for PLP. The methodological quality of most publications in this field is very limited, highlighting the need for additional, high-quality studies to develop clinical protocols that could maximise the benefits of MT for patients with PLP.
Topics: Amitriptyline; Antidepressive Agents, Tricyclic; Gabapentin; Humans; Mirror Movement Therapy; Phantom Limb
PubMed: 36195376
DOI: 10.1016/j.nrleng.2018.08.005 -
European Journal of Pediatrics Oct 2018Cyclic vomiting syndrome (CVS) in children is characterized by frequent hospitalizations, multiple comorbidities, and poor quality of life. In the absence of robust... (Review)
Review
UNLABELLED
Cyclic vomiting syndrome (CVS) in children is characterized by frequent hospitalizations, multiple comorbidities, and poor quality of life. In the absence of robust data, the treatment of CVS remains largely empiric starting with the 2008 NASPGHAN Consensus Statement recommendations of cyproheptadine for children < 5 years of age and amitriptyline for those ≥ 5 years with propranolol serving as the second-line agent. Comprehensive management begins with lifestyle alterations, and extends to medications, supplements, and stress reduction therapies. Standard drug therapy is organized by the four phases of the illness: (1) interictal (preventative medications and mitochondrial supplements), (2) prodromal (abortive agents), (3) vomiting (fluids/energy substrates, antiemetics, analgesics, and sedatives) and (4) recovery (supportive care and nutrition). Because the response to treatment is heterogeneous, clinicians often trial several different preventative strategies including NK1 antagonists, cautious titration of amitriptyline to higher doses, anticonvulsants, Ca-channel blockers, and other TCA antidepressants. When the child remains refractory to treatment, reconsideration of possible missed diagnoses and further mono- or combination therapy and psychotherapy can be guided by accompanying comorbidities (especially anxiety), specific subphenotype, and when available, genotype. For hospital intervention, IV fluids with 10% dextrose, antiemetics, and analgesics can lessen symptoms while effective sedation in some instances can truncate severe episodes.
CONCLUSION
Although management of CVS remains challenging to the clinician, approaches based upon recent literature and accumulated experience with subgroups of patients has led to improved treatment of the refractory and hospitalized patient. What is Known: • Cyclic vomiting syndrome is a complex disorder that remains challenging to manage. • Previous therapy has been guided by the NASPGHAN Consensus Statement of 2008. What is New: • New prophylactic approaches include NK1 antagonists and higher dosages of amitriptyline. • Strategies based upon comorbidities and subphenotype are helpful in refractory patients.
Topics: Adolescent; Analgesics; Anticonvulsants; Antiemetics; Child; Child, Preschool; Comorbidity; Dietary Supplements; Disease Management; Female; Humans; Hypnotics and Sedatives; Male; Vomiting
PubMed: 30076469
DOI: 10.1007/s00431-018-3218-7 -
Journal of Affective Disorders Jul 2015Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence...
BACKGROUND
Dose equivalence of antidepressants is critically important for clinical practice and for research. There are several methods to define and calculate dose equivalence but for antidepressants, only daily defined dose and consensus methods have been applied to date. The purpose of the present study is to examine dose equivalence of antidepressants by a less arbitrary and more systematic method.
METHODS
We used data from all randomized, double-blind, flexible-dose trials comparing fluoxetine or paroxetine as standard drugs with any other active antidepressants as monotherapy in the acute phase treatment of unipolar depression. We calculated the ratio of the mean doses for each study and weighted it by the total sample size to find the weighted mean ratio for each drug, which was then used to define the drug׳s dosage equivalent to fluoxetine 40mg/d.
RESULTS
We included 83 studies (14 131 participants). In the primary analysis, fluoxetine 40mg/day was equivalent to paroxetine dosage of 34.0mg/day, agomelatine 53.2mg/day, amitriptyline, 122.3mg/day, bupropion 348.5mg/day, clomipramine 116.1mg/day, desipramine 196.3mg/day, dothiepin 154.8mg/day, doxepin 140.1mg/day, escitalopram 18.0mg/day, fluvoxamine 143.3mg/day, imipramine 137.2mg/day, lofepramine 250.2mg/day, maprotiline 118.0mg/day, mianserin, 101.1mg/day, mirtazapine 50.9mg/day, moclobemide 575.2mg/day, nefazodone 535.2mg/day, nortriptyline 100.9mg/day, reboxetine 11.5mg/day, sertraline 98.5mg/day, trazodone 401.4mg/day, and venlafaxine 149.4mg/day. Sensitivity analyses corroborated the results except for doxepin.
LIMITATIONS
The number of studies for some drugs was small. The current method assumes dose response relationship of antidepressants.
CONCLUSIONS
Our findings can be useful for clinicians when they switch antidepressants and for researchers when they compare various antidepressants in their research.
Topics: Adult; Amitriptyline; Antidepressive Agents; Bupropion; Citalopram; Depressive Disorder, Major; Dose-Response Relationship, Drug; Double-Blind Method; Evidence-Based Medicine; Female; Fluoxetine; Fluvoxamine; Humans; Male; Middle Aged; Moclobemide; Nortriptyline; Paroxetine; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome
PubMed: 25911132
DOI: 10.1016/j.jad.2015.03.021