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1. Nausea: Duloxetine can cause nausea or vomiting, which may be more common during the first few weeks of treatment.
2. Headache: Duloxetine can cause headaches, which may range from mild to severe.
3. Dry mouth: Duloxetine can cause dry mouth, which can lead to dental problems or other complications.
4. Fatigue: Duloxetine can cause fatigue or tiredness, which can affect daily activities.
5. Constipation: Duloxetine can cause constipation, which can lead to discomfort or other gastrointestinal problems.
6. Dizziness: Duloxetine can cause dizziness or lightheadedness, particularly when standing up quickly.
7. Insomnia: Duloxetine can cause insomnia or difficulty sleeping, particularly in people who take the medication later in the day.
8. Sweating: Duloxetine can cause excessive sweating, which can be uncomfortable or embarrassing.
9. Diarrhea: Duloxetine can cause diarrhea, which can lead to dehydration or other complications.
10. Loss of appetite: Duloxetine can cause loss of appetite or decreased appetite, which can lead to weight loss or other nutritional deficiencies.
11. Sexual dysfunction: Duloxetine can cause sexual dysfunction, such as decreased libido or difficulty achieving or maintaining an erection, particularly in men.
12. Abnormal dreams: Duloxetine can cause abnormal dreams or nightmares, which can affect sleep quality or overall well-being.
13. Anxiety: Duloxetine can cause or worsen anxiety, particularly in people with pre-existing anxiety disorders.
14. Agitation: Duloxetine can cause agitation or restlessness, particularly in people with pre-existing psychiatric conditions.
15. Blurred vision: Duloxetine can cause blurred vision or other visual disturbances, particularly in people with pre-existing vision problems.
16. Chest pain: Duloxetine can cause chest pain or discomfort, particularly in people with pre-existing cardiovascular problems.
17. Confusion: Duloxetine can cause confusion or disorientation, particularly in older adults or people with cognitive impairment.
18. Depression: Duloxetine can cause or worsen depression, particularly in people with pre-existing depressive disorders.
19. Increased risk of suicidal thoughts or behavior: Duloxetine can increase the risk of suicidal thoughts or behavior, particularly in children, adolescents, and young adults.
20. Increased risk of bleeding: Duloxetine can increase the risk of bleeding, particularly in people taking blood-thinning medications.
21. Increased risk of hyponatremia: Duloxetine can cause hyponatremia, which is a condition in which the blood sodium levels are too low and can lead to neurological problems.
22. Increased risk of serotonin syndrome: Duloxetine can increase the risk of serotonin syndrome, which is a potentially life-threatening condition that occurs when the body has an excessive amount of serotonin.
23. Liver toxicity: Duloxetine can cause liver toxicity or liver damage, particularly in people with pre-existing liver problems.
24. Increased risk of glaucoma: Duloxetine can increase the risk of glaucoma, particularly in people with pre-existing eye problems.
25. Increased risk of seizures: Duloxetine can increase the risk of seizures, particularly in people with pre-existing seizure disorders.
26. Increased risk of bone fractures: Duloxetine can increase the risk of bone fractures, particularly in older adults or people with pre-existing osteoporosis.
27. Increased risk of falls: Duloxetine can increase the risk of falls, particularly in older adults or people with pre-existing balance problems.
28. Increased risk of hypertension: Duloxetine can increase blood pressure, particularly in people with pre-existing hypertension.
29. Increased risk of diabetes: Duloxetine can increase the risk of diabetes or worsen blood sugar control, particularly in people with pre-existing diabetes or those at risk for developing diabetes.
30. Increased risk of urinary retention: Duloxetine can increase the risk of uninary retention.
31. Increased risk of urinary incontinence: Duloxetine can increase the risk of urinary incontinence or leakage, particularly in women.
32. Increased risk of weight gain: Duloxetine can cause weight gain, particularly in people who take the medication for an extended period.
33. Increased risk of muscle spasms: Duloxetine can cause muscle spasms or twitching, particularly in people with pre-existing muscle disorders.
34. Increased risk of tinnitus: Duloxetine can cause tinnitus or ringing in the ears, which can be temporary or persistent.
35. Increased risk of skin rash: Duloxetine can cause skin rash or other allergic reactions, particularly in people with pre-existing skin conditions.
36. Increased risk of mania: Duloxetine can cause or worsen mania, particularly in people with pre-existing bipolar disorder.
37. Increased risk of hypomania: Duloxetine can cause or worsen hypomania, which is a milder form of mania.
38. Increased risk of psychosis: Duloxetine can cause or worsen psychosis, particularly in people with pre-existing psychotic disorders.
39. Increased risk of withdrawal symptoms: Duloxetine can cause withdrawal symptoms if the medication is stopped suddenly or if the dosage is reduced too quickly.
40. Increased risk of serotonin discontinuation syndrome: Duloxetine can cause serotonin discontinuation syndrome, which is a set of symptoms that occur when a person stops taking the medication abruptly or reduces the dosage too quickly.
41. Increased risk of liver failure: Duloxetine can cause liver failure or other complications, particularly in people with pre-existing liver problems.
42. Increased risk of heart failure: Duloxetine can cause heart failure or other cardiovascular problems, particularly in people with pre-existing heart disease.
43. Increased risk of stroke: Duloxetine can increase the risk of stroke, particularly in people with pre-existing cardiovascular problems.
44. Increased risk of death in older adults with dementia: Duloxetine can increase the risk of death in older adults with dementia, particularly in those with pre-existing cardiovascular problems.
45. Increased risk of bleeding in the gastrointestinal tract: Duloxetine can increase the risk of bleeding in the gastrointestinal tract, particularly in people with pre-existing gastrointestinal problems.
46. Increased risk of falls in people with peripheral neuropathy: Duloxetine can increase the risk of falls in people with peripheral neuropathy, which is a condition that affects the nerves and can cause numbness, tingling, or weakness in the hands or feet.
47. Increased risk of falls in people with Parkinson’s disease: Duloxetine can increase the risk of falls in people with Parkinson’s disease, particularly in those with pre-existing balance problems.
48. Increased risk of falls in people with multiple sclerosis: Duloxetine can increase the risk of falls in people with multiple sclerosis, particularly in those with pre-existing balance problems.
49. Increased risk of falls in people with cerebellar ataxia: Duloxetine can increase the risk of falls in people with cerebellar ataxia, which is a condition that affects the cerebellum and can cause balance problems or coordination difficulties.
50. Increased risk of falls in people with vestibular disorders: Duloxetine can increase the risk of falls in people with vestibular disorders, which are disorders that affect the inner ear and balance.
51. Increased risk of falls in people with osteoporosis: Duloxetine can increase the risk of falls in people with osteoporosis, which is a condition that causes bones to become weak and brittle.
52. Increased risk of falls in people with muscle weakness: Duloxetine can increase the risk of falls in people with muscle weakness, particularly in those with pre-existing neuromuscular disorders.
53. Increased risk of falls in people with visual impairments: Duloxetine can increase the risk of falls in people with visual impairments, particularly in those with pre-existing eye problems.
54. Increased risk of falls in people with vertigo: Duloxetine can increase the risk of falls in people with vertigo, which is a condition that causes dizziness or a spinning sensation.
55. Increased risk of falls in people with postural hypotension: Duloxetine can increase the risk of falls in people with postural hypotension, which is a condition that causes low blood pressure when standing up.
56. Increased risk of falls in people with peripheral artery disease: Duloxetine can increase the risk of falls in people with peripheral artery disease, which is a condition that affects the circulation in the legs and can cause pain or weakness.
57. Increased risk of falls in people with cerebrovascular disease: Duloxetine can increase the risk of falls in people with cerebrovascular disease, which is a condition that affects the blood vessels in the brain and can cause stroke or other complications.
58. Increased risk of falls in people with chronic kidney disease: Duloxetine can increase the risk of falls in people with chronic kidney disease, particularly in those with pre-existing balance problems.
59. Increased risk of falls in people with chronic obstructive pulmonary disease (COPD): Duloxetine can increase the risk of falls in people with COPD, which is a group of lung diseases that make it difficult to breathe.
60. Increased risk of falls in people with rheumatoid arthritis: Duloxetine can increase the risk of falls in people with rheumatoid arthritis, which is a condition that affects the joints and can cause pain or stiffness.
61. Increased risk of falls in people with lupus: Duloxetine can increase the risk of falls in people with lupus, which is an autoimmune disease that can affect various organs and systems in the body.
62. Increased risk of falls in people with fibromyalgia: Duloxetine can increase the risk of falls in people with fibromyalgia, which is a condition that causes widespread pain and tenderness in the muscles and joints.
63. Increased risk of falls in people with chronic pain: Duloxetine can increase the risk of falls in people with chronic pain, particularly in those who take the medication for an extended period.
64. Increased risk of falls in people with anxiety: Duloxetine can increase the risk of falls in people with anxiety, particularly in those with pre-existing balance problems.
65. Increased risk of falls in people with depression: Duloxetine can increase the risk of falls in people with depression, particularly in those with pre-existing balance problems.
66. Increased risk of falls in people with a history of substance abuse: Duloxetine can increase the risk of falls in people with a history of substance abuse, particularly in those who abuse alcohol or sedatives.
67. Increased risk of falls in people with a history of head injury: Duloxetine can increase the risk of falls in people with a history of head injury, particularly in those with pre-existing neurological problems.
68. Increased risk of falls in people with a history of seizures: Duloxetine can increase the risk of falls in people with a history of seizures, particularly in those with pre-existing neurological problems.
69. Increased risk of falls in people with a history of fainting: Duloxetine can increase the risk of falls in people with a history of fainting or syncope, particularly in those with pre-existing cardiovascular problems.
70. Increased risk of falls in people with a history of low blood pressure: Duloxetine can increase the risk of falls in people with a history of low blood pressure, particularly in those with pre-existing cardiovascular problems.
71. Increased risk of falls in people with a history of stroke: Duloxetine can increase the risk of falls in people with a history of stroke, particularly in those with pre-existing neurological problems or balance issues.
72. Increased risk of falls in people with a history of Parkinson’s disease: Duloxetine can increase the risk of falls in people with a history of Parkinson’s disease, particularly in those with pre-existing balance problems or muscle weakness.
73. Increased risk of falls in people with a history of multiple sclerosis: Duloxetine can increase the risk of falls in people with a history of multiple sclerosis, particularly in those with pre-existing balance problems or muscle weakness.
74. Increased risk of falls in people with a history of cerebral palsy: Duloxetine can increase the risk of falls in people with a history of cerebral palsy, particularly in those with pre-existing balance problems or muscle weakness.
75. Increased risk of falls in people with a history of spinal cord injury: Duloxetine can increase the risk of falls in people with a history of spinal cord injury, particularly in those with pre-existing balance problems or muscle weakness.
76. Increased risk of falls in people with a history of muscular dystrophy: Duloxetine can increase the risk of falls in people with a history of muscular dystrophy, particularly in those with pre-existing muscle weakness or balance problems.
77. Increased risk of falls in people with a history of peripheral neuropathy: Duloxetine can increase the risk of falls in people with a history of peripheral neuropathy, particularly in those with pre-existing balance problems or muscle weakness.
78. Increased risk of falls in people with a history of vestibular disorders: Duloxetine can increase the risk of falls in people with a history of vestibular disorders, particularly in those with pre-existing balance problems or muscle weakness.
79. Increased risk of falls in people with a history of cerebrovascular disease: Duloxetine can increase the risk of falls in people with a history of cerebrovascular disease, particularly in those with pre-existing neurological problems or balance issues.
80. Increased risk of falls in people with a history of chronic obstructive pulmonary disease (COPD): Duloxetine can increase the risk of falls in people with a history of COPD, particularly in those with pre-existing muscle weakness or balance problems.
81. Increased risk of serotonin syndrome: Duloxetine can increase the risk of serotonin syndrome, which is a potentially life-threatening condition that occurs when there is too much serotonin in the body. Symptoms of serotonin syndrome include confusion, agitation, rapid heartbeat, high blood pressure, dilated pupils, muscle rigidity, and fever.
82. Increased risk of hyponatremia: Duloxetine can cause hyponatremia or low levels of sodium in the blood, which can cause symptoms such as headache, nausea, vomiting, seizures, and coma.
83. Increased risk of serotonin reuptake inhibitor (SSRI) discontinuation syndrome: Duloxetine can cause SSRI discontinuation syndrome, which is a set of symptoms that occur when a person stops taking an SSRI abruptly or reduces the dosage too quickly. Symptoms of SSRI discontinuation syndrome include dizziness, nausea, vomiting, headache, insomnia, and anxiety.
84. Increased risk of glaucoma: Duloxetine can increase the risk of glaucoma, which is a condition that affects the eyes and can cause vision loss or blindness.
85. Increased risk of cataracts: Duloxetine can increase the risk of cataracts, which is a condition that affects the eyes and can cause vision loss or blindness.
86. Increased risk of angle-closure glaucoma: Duloxetine can increase the risk of angle-closure glaucoma, which is a type of glaucoma that occurs when the fluid in the eye cannot drain properly, leading to a sudden increase in eye pressure.
87. Increased risk of akathisia: Duloxetine can cause akathisia, which is a feeling of restlessness or agitation that can be uncomfortable or distressing.
88. Increased risk of suicidal thoughts or behaviors: Duloxetine can increase the risk of suicidal thoughts or behaviors, particularly in children, adolescents, and young adults. It is important to monitor for any changes in mood or behavior while taking this medication.
89. Increased risk of sexual dysfunction: Duloxetine can cause sexual dysfunction, such as decreased libido, difficulty achieving or maintaining an erection, or difficulty achieving orgasm.
90. Increased risk of hypospadias: Duloxetine can increase the risk of hypospadias, which is a birth defect that affects the male urethra.
1. Serotonin and Norepinephrine Reuptake Inhibitors
This chapter covers antidepressants that fall into the class of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. That is, they bind to the 5-HT and NE transporters with varying levels of potency and binding affinity ratios. Unlike the selective serotonin (5-HT) reuptake inhibitors (SSRIs), most of these antidepressants have an ascending rather than a flat dose-response curve. The chapter provides a brief review of the chemistry, pharmacology, metabolism, safety and adverse effects, clinical use, and therapeutic indications of each antidepressant. Venlafaxine, a phenylethylamine, is a relatively weak 5-HT and weaker NE uptake inhibitor with a 30-fold difference in binding of the two transporters. Therefore, the drug has a clear dose progression, with low doses predominantly binding to the 5-HT transporter and more binding of the NE transporter as the dose ascends. Venlafaxine is metabolized to the active metabolite O-desmethylvenlafaxine (ODV; desvenlafaxine) by CYP2D6, and it therefore is subject to significant inter-individual variation in blood levels and response dependent on variations in CYP2D6 metabolism. The half-life of venlafaxine is short at about 5 h, with the ODV metabolite being 12 h. Both parent compound and metabolite have low protein binding and neither inhibit CYP enzymes. Therefore, both venlafaxine and desvenlafaxine are potential options if drug-drug interactions are a concern, although venlafaxine may be subject to drug-drug interactions with CYP2D6 inhibitors. At low doses, the adverse effect profile is similar to an SSRI with nausea, diarrhea, fatigue or somnolence, and sexual side effects, while venlafaxine at higher doses can produce mild increases in blood pressure, diaphoresis, tachycardia, tremors, and anxiety. A disadvantage of venlafaxine relative to the SSRIs is the potential for dose-dependent blood pressure elevation, most likely due to the NE reuptake inhibition caused by higher doses; however, this adverse effect is infrequently observed at doses below 225 mg per day. Venlafaxine also has a number of potential advantages over the SSRIs, including an ascending dose-antidepressant response curve, with possibly greater overall efficacy at higher doses. Venlafaxine is approved for MDD as well as generalized anxiety disorder, social anxiety disorder, and panic disorder. Desvenlafaxine is the primary metabolite of venlafaxine, and it is also a relatively low-potency 5-HT and NE uptake inhibitor. Like venlafaxine it has a favorable drug-drug interaction profile. It is subject to CYP3A4 metabolism, and it is therefore vulnerable to enzyme inhibition or induction. However, the primary metabolic pathway is direct conjugation. It is approved in the narrow dose range of 50-100 mg per day. Duloxetine is a more potent 5-HT and NE reuptake inhibitor with a more balanced profile of binding at about 10:1 for 5HT and NE transporter binding. It is also a moderate inhibitor of CYP2D6, so that modest dose reductions and careful monitoring will be needed when prescribing duloxetine in combination with drugs that are preferentially metabolized by CYP2D6. The most common side effects identified in clinical trials are nausea, dry mouth, dizziness, constipation, insomnia, asthenia, and hypertension, consistent with its mechanisms of action. Clinical trials to date have demonstrated rates of response and remission in patients with major depression that are comparable to other marketed antidepressants reviewed in this book. In addition to approval for MDD, duloxetine is approved for diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain. Milnacipran is marketed as an antidepressant in some countries, but not in the USA. It is approved in the USA and some other countries as a treatment for fibromyalgia. It has few pharmacokinetic and pharmacodynamic interactions with other drugs. Milnacipran has a half-life of about 10 h and therefore needs to be administered twice per day. It is metabolized by CYP3A4, but the major pathway for clearance is direct conjugation and renal elimination. As with other drugs in this class, dysuria is a common, troublesome, and dose-dependent adverse effect (occurring in up to 7% of patients). High-dose milnacipran has been reported to cause blood pressure and pulse elevations. Levomilnacipran is the levorotary enantiomer of milnacipran, and it is pharmacologically very similar to the racemic compound, although the side effects may be milder within the approved dosing range. As with other NE uptake inhibitors, it may increase blood pressure and pulse, although it appears to do so less than some other medications. All medications in the class can cause serotonin syndrome when combined with MAOIs.
2. Burning mouth syndrome: a review and update
Burning mouth syndrome (BMS) is mainly found in middle aged or elderly women and is characterized by intense burning or itching sensation of the tongue or other regions of the oral mucosa. It can be accompanied by xerostomia and dysgeusia. The syndrome generally manifests spontaneously, and the discomfort is typically of a continuous nature but increases in intensity during the evening and at night. Although BMS classically has been attributed to a range of factors, in recent years evidence has been obtained relating it peripheral (sensory C and/or trigeminal nerve fibers) or central neuropathic disturbances (involving the nigrostriatal dopaminergic system). The differential diagnosis requires the exclusion of oral mucosal lesions or blood test alterations that can produce burning mouth sensation. Patient management is based on the avoidance of causes of oral irritation and the provision of psychological support. Drug treatment for burning sensation in primary BMS of peripheral origin can consist of topical clonazepam, while central type BMS appears to improve with the use of antidepressants such as duloxetine, antiseizure drugs such as gabapentin, or amisulpride.
3. Bioaccumulation of therapeutic drugs by human gut bacteria
Bacteria in the gut can modulate the availability and efficacy of therapeutic drugs. However, the systematic mapping of the interactions between drugs and bacteria has only started recently1 and the main underlying mechanism proposed is the chemical transformation of drugs by microorganisms (biotransformation). Here we investigated the depletion of 15 structurally diverse drugs by 25 representative strains of gut bacteria. This revealed 70 bacteria-drug interactions, 29 of which had not to our knowledge been reported before. Over half of the new interactions can be ascribed to bioaccumulation; that is, bacteria storing the drug intracellularly without chemically modifying it, and in most cases without the growth of the bacteria being affected. As a case in point, we studied the molecular basis of bioaccumulation of the widely used antidepressant duloxetine by using click chemistry, thermal proteome profiling and metabolomics. We find that duloxetine binds to several metabolic enzymes and changes the metabolite secretion of the respective bacteria. When tested in a defined microbial community of accumulators and non-accumulators, duloxetine markedly altered the composition of the community through metabolic cross-feeding. We further validated our findings in an animal model, showing that bioaccumulating bacteria attenuate the behavioural response of Caenorhabditis elegans to duloxetine. Together, our results show that bioaccumulation by gut bacteria may be a common mechanism that alters drug availability and bacterial metabolism, with implications for microbiota composition, pharmacokinetics, side effects and drug responses, probably in an individual manner.
4. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia
Background: Duloxetine is a balanced serotonin and noradrenaline reuptake inhibitor licensed for the treatment of major depressive disorders, urinary stress incontinence and the management of neuropathic pain associated with diabetic peripheral neuropathy. A number of trials have been conducted to investigate the use of duloxetine in neuropathic and nociceptive painful conditions. This is the first update of a review first published in 2010.
Objectives: To assess the benefits and harms of duloxetine for treating painful neuropathy and different types of chronic pain.
Search methods: On 19th November 2013, we searched The Cochrane Neuromuscular Group Specialized Register, CENTRAL, DARE, HTA, NHSEED, MEDLINE, and EMBASE. We searched ClinicalTrials.gov for ongoing trials in April 2013. We also searched the reference lists of identified publications for trials of duloxetine for the treatment of painful peripheral neuropathy or chronic pain.
Selection criteria: We selected all randomised or quasi-randomised trials of any formulation of duloxetine, used for the treatment of painful peripheral neuropathy or chronic pain in adults.
Data collection and analysis: We used standard methodological procedures expected by The Cochrane Collaboration.
Main results: We identified 18 trials, which included 6407 participants. We found 12 of these studies in the literature search for this update. Eight studies included a total of 2728 participants with painful diabetic neuropathy and six studies involved 2249 participants with fibromyalgia. Three studies included participants with depression and painful physical symptoms and one included participants with central neuropathic pain. Studies were mostly at low risk of bias, although significant drop outs, imputation methods and almost every study being performed or sponsored by the drug manufacturer add to the risk of bias in some domains. Duloxetine at 60 mg daily is effective in treating painful diabetic peripheral neuropathy in the short term, with a risk ratio (RR) for ≥ 50% pain reduction at 12 weeks of 1.73 (95% CI 1.44 to 2.08). The related NNTB is 5 (95% CI 4 to 7). Duloxetine at 60 mg daily is also effective for fibromyalgia over 12 weeks (RR for ≥ 50% reduction in pain 1.57, 95% CI 1.20 to 2.06; NNTB 8, 95% CI 4 to 21) and over 28 weeks (RR 1.58, 95% CI 1.10 to 2.27) as well as for painful physical symptoms in depression (RR 1.37, 95% CI 1.19 to 1.59; NNTB 8, 95% CI 5 to 14). There was no effect on central neuropathic pain in a single, small, high quality trial. In all conditions, adverse events were common in both treatment and placebo arms but more common in the treatment arm, with a dose-dependent effect. Most adverse effects were minor, but 16% of participants stopped the drug due to adverse effects. Serious adverse events were rare.
Authors’ conclusions: There is adequate amounts of moderate quality evidence from eight studies performed by the manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not required. In fibromyalgia, there is lower quality evidence that duloxetine is effective at similar doses to those used in diabetic peripheral neuropathy and with a similar magnitude of effect. The effect in fibromyalgia may be achieved through a greater improvement in mental symptoms than in somatic physical pain. There is low to moderate quality evidence that pain relief is also achieved in pain associated with depressive symptoms, but the NNTB of 8 in fibromyalgia and depression is not an indication of substantial efficacy. More trials (preferably independent investigator led studies) in these indications are required to reach an optimal information size to make convincing determinations of efficacy.Minor side effects are common and more common with duloxetine 60 mg and particularly with 120 mg daily, than 20 mg daily, but serious side effects are rare.Improved direct comparisons of duloxetine with other antidepressants and with other drugs, such as pregabalin, that have already been shown to be efficacious in neuropathic pain would be appropriate. Unbiased economic comparisons would further help decision making, but no high quality study includes economic data.
5. Withdrawal Symptoms after Serotonin-Noradrenaline Reuptake Inhibitor Discontinuation: Systematic Review
Background: Serotonin-noradrenaline reuptake inhibitors (SNRI) are widely used in medical practice. Their discontinuation has been associated with a wide range of symptoms. The aim of this paper is to identify the occurrence, frequency, and features of withdrawal symptoms after SNRI discontinuation.
Methods: PRISMA guidelines were followed to conduct a systematic review. Electronic databases included PubMed, the Cochrane Library, Web of Science, and MEDLINE from the inception of each database to June 2017. Titles, abstracts, and topics were searched using a combination of the following terms: “duloxetine” OR “venlafaxine” OR “desvenlafaxine” OR “milnacipran” OR “levomilnacipran” OR “SNRI” OR “second generation antidepressant” OR “serotonin norepinephrine reuptake inhibitor” AND “discontinuation” OR “withdrawal” OR “rebound.” Only published trials in the English language were included.
Results: Sixty-one reports met the criteria for inclusion. There were 22 double-blind randomized controlled trials, 6 studies where patients were treated in an open fashion and then randomized to a double-blind controlled phase, 8 open trials, 1 prospective naturalistic study, 1 retrospective study, and 23 case reports. Withdrawal symptoms occurred after discontinuation of any type of SNRI. The prevalence of withdrawal symptoms varied across reports and appeared to be higher with venlafaxine. Symptoms typically ensued within a few days from discontinuation and lasted a few weeks, also with gradual tapering. Late onset and/or a longer persistence of disturbances occurred as well.
Conclusions: Clinicians need to add SNRI to the list of drugs potentially inducing withdrawal symptoms upon discontinuation, together with other types of psychotropic drugs. The results of this study challenge the use of SNRI as first-line treatment for mood and anxiety disorders.
Keywords: Adverse events; Antidepressant drugs; Desvenlafaxine; Discontinuation syndrome; Duloxetine; Levomilnacipran; Milnacipran; Serotonin-noradrenaline reuptake inhibitors; Venlafaxine; Withdrawal symptoms.
6. Optimal pharmacotherapy pathway in adults with diabetic peripheral neuropathic pain: the OPTION-DM RCT
Background: The mainstay of treatment for diabetic peripheral neuropathic pain is pharmacotherapy, but the current National Institute for Health and Care Excellence guideline is not based on robust evidence, as the treatments and their combinations have not been directly compared.
Objectives: To determine the most clinically beneficial, cost-effective and tolerated treatment pathway for diabetic peripheral neuropathic pain.
Design: A randomised crossover trial with health economic analysis.
Setting: Twenty-one secondary care centres in the UK.
Participants: Adults with diabetic peripheral neuropathic pain with a 7-day average self-rated pain score of ≥ 4 points (Numeric Rating Scale 0-10).
Interventions: Participants were randomised to three commonly used treatment pathways: (1) amitriptyline supplemented with pregabalin, (2) duloxetine supplemented with pregabalin and (3) pregabalin supplemented with amitriptyline. Participants and research teams were blinded to treatment allocation, using over-encapsulated capsules and matching placebos. Site pharmacists were unblinded.
Outcomes: The primary outcome was the difference in 7-day average 24-hour Numeric Rating Scale score between pathways, measured during the final week of each pathway. Secondary end points included 7-day average daily Numeric Rating Scale pain score at week 6 between monotherapies, quality of life (Short Form questionnaire-36 items), Hospital Anxiety and Depression Scale score, the proportion of patients achieving 30% and 50% pain reduction, Brief Pain Inventory – Modified Short Form items scores, Insomnia Severity Index score, Neuropathic Pain Symptom Inventory score, tolerability (scale 0-10), Patient Global Impression of Change score at week 16 and patients’ preferred treatment pathway at week 50. Adverse events and serious adverse events were recorded. A within-trial cost-utility analysis was carried out to compare treatment pathways using incremental costs per quality-adjusted life-years from an NHS and social care perspective.
Results: A total of 140 participants were randomised from 13 UK centres, 130 of whom were included in the analyses. Pain score at week 16 was similar between the arms, with a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for duloxetine supplemented with pregabalin compared with amitriptyline supplemented with pregabalin, a mean difference of -0.1 points (98.3% confidence interval -0.5 to 0.3 points) for pregabalin supplemented with amitriptyline compared with amitriptyline supplemented with pregabalin and a mean difference of 0.0 points (98.3% confidence interval -0.4 to 0.4 points) for pregabalin supplemented with amitriptyline compared with duloxetine supplemented with pregabalin. Results for tolerability, discontinuation and quality of life were similar. The adverse events were predictable for each drug. Combination therapy (weeks 6-16) was associated with a further reduction in Numeric Rating Scale pain score (mean 1.0 points, 98.3% confidence interval 0.6 to 1.3 points) compared with those who remained on monotherapy (mean 0.2 points, 98.3% confidence interval -0.1 to 0.5 points). The pregabalin supplemented with amitriptyline pathway had the fewest monotherapy discontinuations due to treatment-emergent adverse events and was most commonly preferred (most commonly preferred by participants: amitriptyline supplemented with pregabalin, 24%; duloxetine supplemented with pregabalin, 33%; pregabalin supplemented with amitriptyline, 43%; p = 0.26). No single pathway was superior in cost-effectiveness. The incremental gains in quality-adjusted life-years were small for each pathway comparison [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -0.002 (95% confidence interval -0.011 to 0.007) quality-adjusted life-years, amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline -0.006 (95% confidence interval -0.002 to 0.014) quality-adjusted life-years and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline 0.007 (95% confidence interval 0.0002 to 0.015) quality-adjusted life-years] and incremental costs over 16 weeks were similar [amitriptyline supplemented with pregabalin compared with duloxetine supplemented with pregabalin -£113 (95% confidence interval -£381 to £90), amitriptyline supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £155 (95% confidence interval -£37 to £625) and duloxetine supplemented with pregabalin compared with pregabalin supplemented with amitriptyline £141 (95% confidence interval -£13 to £398)].
Limitations: Although there was no placebo arm, there is strong evidence for the use of each study medication from randomised placebo-controlled trials. The addition of a placebo arm would have increased the duration of this already long and demanding trial and it was not felt to be ethically justifiable.
7. Is duloxetine an alternative in the treatment of osteoarthritis?
Introduction: Many osteoarthritis patients continue to present symptoms despite nonsurgical treatment. Duloxetine might be a viable alternative for such cases, but real clinical relevance remains unclear.
Methods: A literature review was conducted in Epistemonikos, the largest database for systematic reviews in health that compiles multiple sources, including MEDLINE, EMBASE, and Cochrane, among others. Relevant data were extracted, and information from the primary studies was reanalyzed. A subsequent meta-analysis was conducted, and summary of findings tables were constructed using the GRADE methodology.
Results and conclusions: Four systematic reviews including four randomized trials, were identified. In conclusion, while duloxetine slightly improves pain and functionality in osteoarthritis patients, its use is associated with frequent adverse side effects. Therefore, the benefit/risk balance appears unfavorable.
8. A randomized comparative study of methylcobalamin, methylcobalamin plus pregabalin and methylcobalamin plus duloxetine in patients of painful diabetic neuropathy
Context: Diabetic neuropathy affects 10.5%-32.2% of diabetic population posing clinical burden onto society.
Aims: We aimed to study the efficacy, safety, and tolerability of methylcobalamin, methylcobalamin plus pregabalin, and methylcobalamin plus duloxetine in patients of painful diabetic neuropathy.
Settings and design: It is a prospective, randomized, open-label, interventional, and parallel-group study done in patients of painful diabetic neuropathy.
Materials and methods: A total of 100 patients were recruited and randomized to three study groups A, B, and C on methylcobalamin, methylcobalamin and pregabalin, and methylcobalamin and duloxetine, respectively. Patients were assessed at day 0 and 4, 8, and 12 weeks. The tuning fork test, monofilament test, Thermal Sensitivity testing, and Visual Analog Scale (VAS) were used to analyze vibration, pressure, thermal sensitivity, and pain.
Statistical analysis used: The results are expressed as mean ± standard deviation. Appropriate statistical methods were used to calculate P value (<0.05 – significant).
Results: The increase in number of patients with vibration perception is 11.6%, 37.9%, and 41.4%; pressure sensation is 7.6%, 37.9%, and 37.9%; and thermal sensitivity is 15.4%, 31.1%, and 37.9% in Groups A, B, and C, respectively. The decrease in VAS scores is 0.58 ± 0.14, 3.82 ± 0.05, and 4.17 ± 0.48 in Groups A, B, and C correspondingly. The adverse effects reported in Groups A, B, and C are 0%, 6.9%, and 10.3%, respectively.
Conclusions: Group C is more efficacious when compared to Groups A and B while Group B is safer.
9. Duloxetine Induced Hyponatremia
Hyponatremia can be asymptomatic or have a wide range of clinical presentations such as headaches, muscle cramps, nausea, seizures, coma, cerebral edema and may even result in death. Despite it has been suggested that duloxetine has a relatively less risk of hyponatraemia, the number of case reports are increasing. A 45- year old female patient with complaints of fear, anxiety, sleeplessness and headache was started on duloxetine (30 mg/day). In the first week of the treatment, she was admitted to the emergency service with dizziness, dry mouth, polyuria and polydipsia. She had to be transferred to the intensive care unit because of agitation, loss of consciousness and a generalized tonic-clonic seizure. Blood levels of Sodium (Na+), Potassium (K+) and Chlorine (Cl-) were, respectfully, 121 mmol/L, 2.7 mmol/L and 87 mmol/L. Brain imaging displayed cerebral edema. Electrolyte levels were regulated with saline infusions. Amitriptyline was initiated for the ongoing headache and anxiety. In outpatient visits, hyponatremia did not recur in the following 3 months. Low dose duloxetine was associated with severe hyponatremia signs and symptoms in an individual who was not previously considered as high risk for hyponatraemia. The patient’s history did not reveal any complaints related to hyponatremia when she was treated with sertraline two years ago. Based on these, we discussed the risk factors for hyponatremia and risky antidepressant classes.
10. Efficacy and safety of duloxetine in chronic musculoskeletal pain: a systematic review and meta-analysis
Background: Chronic musculoskeletal pain (CMP) is a complex condition that is mainly treated with analgesic drugs. However, antidepressant intervention is also an important factor in the treatment of CMP. Duloxetine is an effective treatment option for patients with CMP as its antidepressant effect. The purpose of this article is to evaluate the efficacy and safety of duloxetine in treating CMP.
Databases and data treatment: We searched PubMed, Web of Science, Embase, Cochrane Library from inception to May, 2022. Randomized controlled trials (RCTs) evaluating the efficacy and safety of duloxetine versus placebo in patients with CMP were included. We identified 13 articles and studied a population of 4201 participants in 4 countries.
Results: This meta-analysis showed that the duloxetine has statistically significant compared with the placebo control, benefits on 24-hour average pain, living quality, physical function, and global impressions and there was no difference in the incidence of serious adverse event. In general, duloxetine can improve mood and pain level at the same time.
Conclusions: This review shows a significant contribution of duloxetine to CMP symptom relief. This meta-analysis improved that duloxetine can significantly reduce the pain level of patients, improve depressive symptoms and global impression, and has no obvious serious adverse reactions. However, additional studies are required to confirm the relationship between psychological diseases and chronic pain and explore their internal links.