Cymbalta Duloxetine Withdrawal

Step by step Cymbalta instructions are on this website.

Cymbalta is a brand name for the medication duloxetine, which is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) commonly used to treat major depressive disorder, generalized anxiety disorder, fibromyalgia, and chronic pain. While Cymbalta is an effective medication for many people, it can also have significant side effects and withdrawal symptoms when the medication is discontinued.

If you are experiencing brain zaps, electrical jolts in the head, click here

If you wish to remain on Cymbalta but eliminate current Cymbalta withdrawal side effects, click here.

If you want to taper off the Cymbalta and you are not sure where to start, you can click here and read the bestselling book, How to Get Off Psychoactive Drugs Safely or send Jim Harper an email at and he will guide you through the process of Cymbalta withdrawal.

Cymbalta withdrawal can be a challenging experience for people who have been taking the medication for an extended period of time, and it can be a difficult process to navigate.

Symptoms of Cymbalta Withdrawal

Cymbalta withdrawal symptoms can vary widely from person to person, but some common symptoms include:

Dizziness: Many people experience dizziness or lightheadedness when they stop taking Cymbalta.

Nausea: Nausea is another common symptom of Cymbalta withdrawal. Some people may also experience vomiting or diarrhea.

Headaches: Headaches are a common symptom of withdrawal from many medications, including Cymbalta.

Insomnia: Many people have difficulty sleeping when they stop taking Cymbalta.

Anxiety: Cymbalta is commonly used to treat anxiety, so it is not surprising that anxiety is a common symptom of withdrawal.

Irritability: People who are experiencing Cymbalta withdrawal may feel more irritable or easily frustrated than usual.

Brain zaps: One of the most distinctive symptoms of Cymbalta withdrawal is the sensation of "brain zaps," which are brief electric shock-like sensations that occur in the head.

Flu-like symptoms: Some people may experience flu-like symptoms such as fatigue, muscle aches, and chills.

Suicidal thoughts: While rare, some people may experience suicidal thoughts or behaviors when they stop taking Cymbalta.

These symptoms can be challenging to manage, and it is important for people who are experiencing Cymbalta withdrawal to seek medical attention if they are having difficulty coping with their symptoms.

Causes of Cymbalta Withdrawal

The causes of Cymbalta withdrawal are not entirely clear, but they are believed to be related to changes in the levels of serotonin and norepinephrine in the brain. Cymbalta works by inhibiting the reuptake of these neurotransmitters, which increases their availability in the brain.

When a person stops taking Cymbalta, the levels of serotonin and norepinephrine in the brain decrease rapidly. This can lead to a variety of symptoms, including the symptoms listed above.

In addition to changes in neurotransmitter levels, Cymbalta withdrawal may also be related to changes in the levels of other hormones and chemicals in the body. For example, Cymbalta may affect the levels of cortisol, a hormone that is involved in the body's response to stress. Changes in cortisol levels could contribute to some of the symptoms of Cymbalta withdrawal, such as anxiety and irritability.

Methods of Treatment for Cymbalta Withdrawal

There are several methods of treatment for Cymbalta withdrawal, including medication, therapy, and lifestyle changes.

One of the most common treatments for Cymbalta withdrawal is the use of The Road Back Program. Cymbalta is known to overly activate the JNK gene and in so doing, the body reacts to the Cymbalta ingestion and the JNK activation leads to further body symptoms. The Road Back Program addresses these issues by using nutritional supplements to not only reduce the JNK activation but other common Cymbalta withdrawal side effects.

Cymbalta Withdrawal Solution, Duloxetine Side Effects, Treatment Options

Cymbalta Withdrawal Symptoms

The majority of people attempting Cymbalta withdrawal experience an antidepressant withdrawal syndrome. This is also known as Cymbalta discontinuation syndrome in the United States. In Europe it is call Cymbalta withdrawal side effects.

The F.D.A. estimates 10% of those experiencing Cymbalta withdrawal will go back up on the Cymbalta because the withdrawal symptoms are too severe. If you want to read the short version of how to handle Cymbalta withdrawal side effects Click here. Page opens new browser window.

The most common and debilitating Cymbalta withdrawal side effect is called "brain zaps." Brain zaps are described by people experiencing it as a; electrical jolt that tends to run from base of the neck up into their head. Another side effect that tends to run with brain zaps is a shiver, a feeling as your head is floating, dizziness, and/or a whirling sensation in the head. These symptoms can come in waves or even be persistent. The good news; in 2002, our founder, Jim Harper, discovered the correct type of Omega 3 taken in the right quantity will eliminate these devastating head symptoms quickly. Usually within a couple of hours. The body in a normal state uses the oil from our diet, specifically from omega 3 found in fish, to build and replenish the end point of areas in the brain that sends and receives electrical signals. We are using easy to understand terminology here so it is easy to understand. Let's leave the technical jargon to physicians. These brain zaps have nothing to do with serotonin levels or other made up reasons.

It is simple really; our body works in a very natural way with how it uses amino acids, proteins, fats in food and all other diet items to maintain a balance. When you introduce any toxin that disrupts these processes the body reacts. The most common Cymbalta Duloxetine withdrawal symptoms reported include:

Flu like symptoms


Brain zaps




Increased suicidal ideation





Ringing in the ears




Mood swings

Please note: These are the most common Cymbalta withdrawal side effects but far from all potential Cymbalta withdrawal side effects. There is a warning the FDA has put a black box warning on Cymbalta. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning.
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients (5.1) Closely monitor for clinical worsening and emergence of suicidal thoughts and behaviors.

You may have been prescribed Cymbalta within a very short doctor visit. There was no investigation into other life factors, lab testing, or any conversation about what side effects might present. The failings of this approach may cause quite a burden on the patient.

Depression, insomnia, anxiety, fibromyalgia, and other symptoms that Cymbalta is often prescribed for might stem from; diminished vitamin D levels, over active JNK gene, specific proteins that need to be silenced, dietary concerns and food allergies, mitochondrial dysfunction, neurotoxic accumulation, and many other reasons. A full physical from an understanding physician is ideal, before prescribing Cymbalta.

Do Your Symptoms Require Cymbalta?

The Road Back Program uses nutritional supplements to help with the Cymbalta withdrawal. Most people feel a very fast relief from the Cymbalta withdrawal once they begin taking the supplements and we feel the odds are high; if would have taken nutritional supplements like these before starting the Cymbalta you would not have been prescribed the Cymbalta in the first place.

In 2007, Jim Harper was giving a speech to a group of psychiatrists in Ireland and during his talk he mentioned his mother just passed away 30 days ago. He went on to describe how he made sure to take his JNK Formula each day to help the body cope with the stress being put on it do to his loss. He went on to say, "The JNK Formula will not remove the emotional loss and how I feel but it will keep the body strong during my time to grieve.

"How Do You Survive Cymbalta Withdrawal?

Surviving Cymbalta withdrawal depends on what you do at this very moment. If you keep doing the same thing you have been doing and you are in a heavy Cymbalta withdrawal, nothing will change for the positive, That is a given. If you decide to do the Cymbalta withdrawal as an inpatient in a drug rehab center DO NOT DO THE 9 DAY PLAN BECAUSE THAT’S WHAT INSURANCE ALLOWS. Over the past 22 years I have worked with far too many people who were sold on a rehab facility, stayed the 9 days because insurance would only pay for that amount of time. The unscrupulous facility took them off the Cymbalta in 9 days as they promised and by the time the person got off the airplane after their return home they were in full withdrawal. You can't do a Cymbalta withdrawal in 9 days.

The Road Back Program can normally help you get back on your feet again but the rehab facility approach of this type is not worth the price you will pay mentally and physically. You will find a few other outpatient Cymbalta withdrawal programs on the internet now and Jim Harper is not aware of one that will cause you harm like the rehab facility's mentioned. However, every other program on the internet was trained by Jim Harper years ago and they are doing what Jim Harper and The Road Back did during that time frame. Almost 2 decades ago Jim Harper trained several physicians and good intentioned people how to get a patient off Cymbalta. Jim went into detail of the process and what nutritional supplements were used and why they were used. At that time of The Road Back the success rate was not as high as desired and over the following years Jim changed the formulas used with the supplements several times to use new information with DNA testing.
Long story short; you will likely wind up using a Cymbalta withdrawal approach The Road Back used in 2003, that was scrapped for something more successful. If you are currently in Cymbalta withdrawal, send Jim Harper an email and he will personally guide you through the process so you can get back on your feet quickly and have a very successful Cymbalta withdrawal. It does not matter if you have been on Cymbalta for 1 month or 20 years. Recovery can happen and the good part is; it does not take more time because you have been taking Cymbalta for years.

When Do Cymbalta Withdrawal Symptoms Start When Discontinuing / Quitting Cymbalta?

Cymbalta withdrawal usually begins between day 1 and day 3 of adjusting the Cymbalta. For some people this is not the case but eventually most everyone hits some dosage of the Cymbalta when reducing that jars them. Cymbalta withdrawal begins and they have no idea what they should do. Their physician does not know what to do. They wind up in a spiral downward and wind up on a new medication to try and stop the Cymbalta withdrawal. The best case is the additional drug does that but you are now on 2 drugs instead of only Cymbalta.

What is Cymbalta?

This SSRI drug is prescribed in treating adult depressive disorders (MDD), panic disorder, obsessive compulsory disorders (OCD), social anxiety (SAD), post-traumatic stress disorders (PTSD), and premenstrual dysphoric disorder (PMDD). If you have anxiety before taking Cymbalta, or anxiety begins while taking Cymbalta, odds are the anxiety will continue to get worse. Cymbalta alters dopamine much like the antidepressant Effexor and anxiety is a byproduct of these two drugs.

What Is Cymbalta Used For? Cymbalta is an antidepressant medication approved to treat adult MDD (major depressive disorder). The Black Box warning on the drug’s packaging mentions that the drug should not be prescribed to anyone under the age of 25, due to heightened risk of suicide. There is an exception to this for patients under the age of 25 who have been diagnosed with OCD (obsessive-compulsive disorder). Potential suicidality is associated with all Cymbalta and may be a concern leading to consider Cymbalta withdrawal, which is recommended to be done always under medical or caregiver monitoring. Adult-only approved uses for the drug provided in a clinical or treatment setting include: MDD: Major Depressive Disorder< PTSD: Post-traumatic stress disorder PD: Panic disorder SAD: Social anxiety disorder OCD: Obsessive-compulsive disorder PMDD:

Premenstrual dysphoric disorder

Cymbalta Side Effects The full list of Cymbalta side effects is quite staggering. In 2004, Jim Harper used the Freedom of Information Act to get the full list of Cymbalta side effects. Jim received the information and it is 500 sheets of letter size paper, single space, a number 10 font size, 3 columns per page. In other words, thousands of known potential Cymbalta side effects were disclosed. Some of the other Cymbalta and Cymbalta withdrawal side effects: Serotonin syndrome: A life-threatening condition requiring immediate medical care in a hospital emergency clinic or ICU. Symptoms to watch for include sudden fever, losing consciousness, inability to move or speak, copious sweating, dilated pupils, chills, tremors, convulsions, diarrhea, agitation, restlessness, racing heart, etc. Suicidal thoughts (common) Suicide attempt (common) Hyperkinesis (muscle spasms, movement disorder) Worsened depression Aggression Paranoia (rare) Anxiety Mania (common) Convulsions Unconsciousness Coma Teeth grinding Akathisia (relentless internal restlessness and discomfort marked by repeated motions, pacing, rocking, etc., that can lead to suicidal thoughts as a means of relief) Tachycardia (racing heart, even when the body is at rest) Rash Itching Burning, crawling feeling in the skin Fever Tics, sudden jerky movements, myoclonus Emotional blunting Behavioral apathy, SSRI-induced-indifference Pain on urination or difficulty urinating Cloudy urine Headache Sexual impairments, i.e., anorgasmia, inability to ejaculate, lowered libido Mood swings Pain around the eyes or eye sockets Sleepiness Bladder pain Prickling skin sensation Numbness Sensory disturbances Insomnia Depersonalization (common) Nervousness Nightmares (paranoia) Hostility Nausea Diarrhea Weight gain Some documented Cymbalta birth defects and injuries include: PPHN or persistent pulmonary hypertension of the newborn, a heart and lung condition which can result in respiratory failure, decreased oxygen to the brain, and multiple organ injuries. Congenital Heart Defects connected to Cymbalta and other SSRIs include ventricular septal defects and atrial septal defects, also referred to as “holes in the heart”, related to heart murmurs, suppressed appetite, breathing difficulties, tiredness, inadequate growth, etc. Increased Risk of Autism has been extensively reported but evidence has not yet been considered conclusive enough for regulatory bodies to ban prescribing to pregnant women. Increased Risk of Clubfoot connected to SSRIs during pregnancy as reported by NIMH, where sertraline exposure had the highest increase in clubfoot of all SSRIs. Increased risk of atrial/ventricular defects and craniosynostosis was reported in a Canadian study from 1998 to 2010 and published in the June 2015 issue of the American Journal of Gynecology & Obstetrics.

Cymbalta Withdrawal, What to Expect

If using The Road Back Program you should expect to feel a lot better within the first couple days of the program. If you do nothing, expect to continue to feel as you do now. Possibly worse as time goes on. The chance of feeling better if you do nothing is nil.

In 1999, The Road Back only had people taper antidepressants gradually and slowly. They still suffered. Around 50% could get off the antidepressant but most went back on the medication because of the withdrawal side effects. We wish there was a better answer for you than the above but with working with over 19 million people over the last 23 years, the truth is the truth. No way to water it down to make it sound better. Some may think it is just their depression returning but who would not feel depressed if they were still going through Cymbalta withdrawal months after stopping the Cymbalta.

We can't stress enough; what you do or do not do at this moment in time is critical for your future. Take your time if at all possible. If you have brain zaps go buy any omega 3 fish oil, even the wrong omega 3 fish oil will help somewhat. While you read this you may want to pause and go take a walk. Look at the trees, the sky or anything off in the distance. Getting your attention off your mind and body may do wonders.

Keep this close to your heart; There is Hope and There is a Solution. We are speaking directly to YOU.A 30 day supply of the nutritional supplements will cost you around $80. If you feel it is worth $80 to take a chance that all of this can go away in a couple of days, then take that chance. Over the past 22 years many have sent an email to Jim Harper and said they were not sure what to do about the Cymbalta withdrawal. Even after reading this information. The people that tried something else generally came back within a few months and were in worse shape than before. We do not want this to happen to you. Jim will still be here to assist.

Can Cymbalta Make Depression Worse?

Common sense answers this question. If depression is one side effect of taking Cymbalta then Cymbalta can cause depression. You do stand a greater chance of Cymbalta causing depression during withdrawal than while simply taking the Cymbalta as prescribed. The depression during Cymbalta withdrawal can be due to the other Cymbalta withdrawal side effects you are experiencing. Who would not start to get depressed if you have anxiety from morning to night, can't sleep and your head feels like it is on fire.
Can You Get Addicted to Cymbalta?

Yes and no. This is where Cymbalta dependence is a matter of wording. Medically speaking in the United States Cymbalta is not addicting. In Europe it is viewed as addicting. The bottom line is; Once you take Cymbalta for 7 days the Cymbalta has made its way through your body. If your body no longer has the Cymbalta in its system, your body will react to the Cymbalta being gone. Much like a person that eats a lot a sweets every day. Your body will react when the sweet substance is not present. Call it addicting, as we would, call it a dependence as United States physicians will, it is what it is. If you do not provide the substance the body reacts and you also have mental feelings that are not positive. We can get into the insulin discussion etc, but we are only talking about a substance being present and then not and the body and mind reacting in a negative manner.

What is the difference between Cymbalta and a Benzodiazepine?

Cymbalta is an SSRI medication, an antidepressant, used to treat depression and anxiety. Benzodiazepines are prescribed mainly for the treatment of anxiety and panic disorders but also prescribed off-label to treat depression. These two types drug have different chemical components and were designed to work on different brain receptors and neurotransmitters, but some of their effects can be seen to overlap. Benzodiazepines are thought to mainly affect GABA transmission, which can slow the central nervous system to reduce anxiety, while Cymbalta is designed to block the reuptake of serotonin. Benzodiazepines are known to be more prone to dependence/addiction than Cymbalta. While the withdrawal symptoms are similar between both drugs, Cymbalta’s half-life is 22-36 hours, and Benzodiazepines half-life is much lower. Benzodiazepines can have more severe complications if abruptly stopped, including seizures. For safe Benzodiazepine or Cymbalta withdrawal, either of these drugs must be slowly tapered to allow the central nervous system and neurochemistry to safely normalize.

Choosing to withdrawal from the Cymbalta first or the benzodiazepine first needs to be evaluated. Use Chapter 23, The Science to decide is part of that equation. Depending on the benzodiazepine you may be taking with the Cymbalta, if you reduce the Cymbalta first it may make you go into withdrawal on the benzodiazepine, even if you did not reduce the benzodiazepine.

How long does Cymbalta stay in your system after the last dosage? Our founder, Jim Harper, made great strides with determining this question. Using his DNA testing company in 2004-2005, Jim conducted hundreds of DNA tests to determine how fast or slow medications took to metabolize. In roughly 34 percent of the population the Cymbalta can take as long as 48 hours to clear the body. In others, as little as 8 hours can occur for the Cymbalta to clear the body. Depending on other habits you may have, Cymbalta could clear faster or even take more time than the 48 hours. If you smoke cigarettes and stop smoking while taking Cymbalta, the Cymbalta dosage you are taking will decrease by 15%. On the other side of this, if you start smoking while taking Cymbalta, the Cymbalta dosage will act as though it is 15% higher than you think it is. This is because cigarettes induce an enzyme used to metabolize Cymbalta and anything using that same pathway will shoot though much faster. Caffeine restricts that same enzyme, so if you start or stop drinking coffee while taking Cymbalta you will either go into withdrawal or feel an overdose, even though you have not changed the Cymbalta dosage. This is why The Road Back Program wants you to not change smoking habits or caffeine habits during the Cymbalta taper.

Can you overdose on Cymbalta?

Yes, it is definitely possible for Cymbalta poisoning to occur. A substantial Cymbalta overdose requires emergency medical intervention to prevent major health problems. This list of Cymbalta overdose symptoms would be the same as those Cymbalta side effects listed above, but more severe. According to the National Institute of Health (NIH), the use of intravenous benzodiazepines is sometimes required during Cymbalta overdose to prevent seizures. Extra cooling measures must be used to reduce hyperthermia, always under the direction of EMT or other medical staff attending to the patient.

Treatment for Cymbalta Withdrawal

Cymbalta has become one of the most frequently prescribed antidepressants in the US. Of equal importance is that depressive disorders have become one of the most frequently diagnosed conditions. These two facts together underscore two important steps toward improved health:

Providing safe treatment programs for those who have decided on Cymbalta withdrawal, and Offering drug-free options to regain natural mental health without the need for prescription medications.

The Road Back Program was described by Dr. Hyla Cass M.D. in this way:

Here's an essential handbook on how to safely and more easily wean yourself (under medical supervision) off the heavily over-prescribed psychotropic medications. I have used the program with my patients and it works!" Hyla Cass M.D. Author of Supplement Your Prescription

Send an email to Jim Harper by using the Contact link on the top of this page or read How to Get Off Psychoactive Drugs Safely by Jim Harper and follow the program for Cymbalta withdrawal.

Why Jim put his entire book on our website for free is so you can instantly read the material and start this process if you are ready now. One last thing Jim asked us to provide at the bottom of each page of Cymbalta descriptions:

There is Hope and There is a Solution]

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 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.