- Depression and attempted suicide under pregabalin therapy
- New Cochrane evidence on pregabalin
- Pain reduction for some
- How much pain reduction is worthwhile?
- Possible harms
- Benefits and harms: a personal balancing act
- A complex reality
- WHAT TO EXPECT WITH LYRICA
- TERMS AND CONDITIONS
- Pregabalin Approved for Generalized Anxiety Disorder in Europe
Depression and attempted suicide under pregabalin therapy
The patient we present is a 20-year-old male admitted to our psychiatric ward in February who reported depressed mood, loss of motivation, hopelessness, anxiety, sleep disturbances, and suicidal thoughts as major depressive symptoms.
Recent brain imaging, as well as routine laboratory analysis upon admission, was unremarkable.
It was the patient’s first episode of a psychiatric disorder. It originally started with somatic symptoms and their treatment. He suffered from an orofacial dyskinesia of unknown origin, muscular atrophy of the right forearm, and an alar scapula on the left, currently diagnosed as multifocal motoric neuropathia. The orofacial dyskinesia was first treated symptomatically with tiapride starting in July the year before admission, which he tolerated well. Later, the movements were thought to be complex-focal seizures, the medication was switched to pregabalin, 150 mg daily within 2 weeks during his stay in an external clinic in October. The patient reported no further co-medication at that time.
Starting with the first prescription of pregabalin in October, the patient felt increasingly depressed (visual analogue scale 4/10–5/10) and demotivated. Suicidal thoughts first appeared in November. These continued to worsen and led to a suicide attempt in December of the year before admission; he tried to poison himself to death using high doses of ibuprofen and aspirin after consuming alcohol. He could not name any triggering factors and described the incident as a completely unexpected and irrational act. He was seen by his general practitioner and taken care of by his family. He did not receive further inpatient treatment then but was prescribed antidepressants for the emerging mood disorder starting with the sedating mirtazapine 15 mg at night in order to prevent further harmful acts on impulse. Later, the serotonergic drug citalopram was added in order to address the lack of motivation, starting with 10 mg and rising to 20 mg in the morning. Tiapride was also restarted for controlling the dyskinesia.
After the patient retrospectively clearly correlated the start of pregabalin therapy with the onset of his depressive symptoms during exploration on our ward, we immediately discontinued the drug. Consequently, he reported a rapid decline in depressive symptoms, his mood remained stable, and he was discharged. Until then, pregabalin was not believed to trigger the patient’s symptoms, and his somatic problems were the focus of investigation and treatment. Thus, there are unfortunately no objective follow-up scales available but only symptom descriptions. His alcohol intake preceding the suicide attempt may be considered a confounding factor. However, casual drinking before taking the drug never caused suicidal thoughts prior to this episode. The depressive symptoms themselves began only when the drug was started; thus, alcohol might have had an aggravating effect.
The introduction of an anticonvulsant, which has efficacy against anxiety, represents a novel treatment strategy for generalised anxiety disorder. Previous studies have reported effectiveness for pregabalin in people with seizure disorders and neuropathic pain.1,2 Pregabalin is similar structurally to gabapentin, but is three to ten times more potent as a GABA analogue than gabapentin.3
A reduced side effect burden is implied by this research. Current treatments for anxiety disorders have significant disadvantages. If buspirone or selective serotonin reuptake inhibitors (SSRIs) are used, people with anxiety disorders must expect a two week to two month delay in the onset of therapeutic benefit. High rates of sexual dysfunction are common with SSRI compounds. The authors have reported a much lower rate of sexual dysfunction and a more rapid onset of action with pregabalin.
The clinician may simplify his practice. Anxiety disorders usually require long term treatment. People taking benzodiazepines as prescribed may be reluctant to agree to discontinuation trials. Many cannot do this without re-emergence of anxiety. Pregabalin was found to have a lesser risk for withdrawal symptoms than lorazepam. Tapering pregabalin should be more acceptable to patients. Re-evaluation of the patient’s continued need for treatment is thus facilitated.
Treatment with pregabalin should generalise to people with multiple illnesses. Anxious individuals with comorbid pulmonary disease or dementia are ordinarily poor candidates for benzodiazepines. Non-benzodiazepine, non-antidepressant anxiolytics are needed in people with bipolar disorder with substance abuse and high potential for destabilisation with antidepressants. Pregabalin has the advantages of no known medication interactions3 and low potential for withdrawal symptoms.4
Is pregabalin an effective anxiolytic? The low effect size, the brief study period, and the high placebo response rate mandate further investigations. This research provides optimism, however, for improved treatment of the many people that suffer from anxiety.
- ↵ French JA, Kugler AR, Robbins JL, et al. Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology 2003;60:1631–7.
- ↵ Dworkin RH, Corbin AE, Young JP Jr, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2003;60:1274–83.
- ↵ Lauria-Horner BA, Pohl RB. Pregabalin: a new anxiolytic. Expert Opin Investig Drugs 2003;12:663–72.
- ↵ Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry 2003;160:533–40.
In this blog, Sarah Chapman looks at the latest Cochrane evidenceCochrane Reviews are systematic reviews. In systematic reviews we search for and summarize studies that answer a specific research question (e.g. is paracetamol effective and safe for treating back pain?). The studies are identified, assessed, and summarized by using a systematic and predefined approach. They inform recommendations for healthcare and research. on the benefits and harms of pregabalin for neuropathic pain and reflects on her husband’s experience of finding a balance between them.
I suspect that people who live with chronic health conditions know a lot about balance. About the trade-offs that need to be considered when it comes to activities, perhaps; about adjustments made to diet, rest or medication to keep things level, or at least within the realms of what feels acceptable. Adding a new treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. threatens that balance. There is the hope it will bring benefits, but it might cause unwelcome side-effects. Here’s a new thing to juggle.
I’ve seen this up close over the past year, as my husband Tim has been living with neuropathic pain. Neuropathic pain comes from nerve damage, from a variety of causes and sometimes an unknown cause. It may not respond well to what we think of as ‘painkillers’ and other types of drugs may be tried. When Tim found no relief with various painkillers, his GP suggested pregabalin, an anti-epileptic drug that can be effective for relief of neuropathic pain. Can be. It’s also associated with side-effects, especially dizziness and sleepiness, and Tim has had rather too much experience of dizziness as a result of another condition. Yet he was willing to chance it. “At this point, I was awake for much of the night in intense pain, too tired to stand up and in too much pain to lie down. I was in a very difficult place. I was prepared to take anything that was offered, and I’d heard good things about pregabalin from health professional colleagues. I was warned by my GP about side-effects but I’d have taken bigger risks to get rid of the pain.”
So began a period of juggling, trying to find the right balance. Months down the line, we were very interested to see the publication of a Cochrane Review on the benefits and harms of pregabalin for adults with neuropathic pain. What information would this offer for others making decisions about taking it?
New Cochrane evidence on pregabalin
The review includes 45 studies (lasting two to 16 weeks) with almost 12000 adults. Most people had postherpetic neuralgia (pain after shingles), diabetic neuropathy or mixed neuropathic pain and the review looks at the evidence for people grouped by condition and also altogether. Oral pregabalin at daily doses of 150mg, 300mg and 600mg were compared with placeboAn intervention that appears to be the same as that which is being assessed but does not have the active component. For example, a placebo could be a tablet made of sugar, compared with a tablet containing a medicine..
Pain reduction for some
The bottom line of the review is that oral pregabalin is helpful for some people with chronic neuropathic pain, but it isn’t possible to know who will benefit and who won’t. At doses of 300mg and 600mg, it probably has an important effect in some people with moderate or severe neuropathic pain after shingles or due to diabetes, and it may be effective for some after trauma due to stroke or spinal cord injury. It is probably not effective for pain in people with HIV. There isn’t reliable evidence on the effects of pregabalin on other types of neuropathic pain.
How much pain reduction is worthwhile?
A very personal consideration perhaps, but pain intensity reduction of at least 50% has been identified as a useful treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. outcomeOutcomes are measures of health (for example quality of life, pain, blood sugar levels) that can be used to assess the effectiveness and safety of a treatment or other intervention (for example a drug, surgery, or exercise). In research, the outcomes considered most important are ‘primary outcomes’ and those considered less important are ‘secondary outcomes’. by people with chronic neuropathic pain and is associated with important benefits for sleep, fatigue, depression, work and quality of life. The evidence in the review suggests that more than half of those taking pregabalin won’t get this much pain relief: around three or four people out of ten, compared with one or two taking placeboAn intervention that appears to be the same as that which is being assessed but does not have the active component. For example, a placebo could be a tablet made of sugar, compared with a tablet containing a medicine..
The review has high-certaintyThe certainty (or quality) of evidence is the extent to which we can be confident that what the research tells us about a particular treatment effect is likely to be accurate. Concerns about factors such as bias can reduce the certainty of the evidence. Evidence may be of high certainty; moderate certainty; low certainty or very-low certainty. Cochrane has adopted the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation) for assessing certainty (or quality) of evidence. Find out more here: https://training.cochrane.org/grade-approach evidence about harms, so the review authors feel confident that future research is not likely to paint a very different picture, although they note that the effects of pregabalin on sexual function may not be well represented in the trialsClinical trials are research studies involving people who use healthcare services. They often compare a new or different treatment with the best treatment currently available. This is to test whether the new or different treatment is safe, effective and any better than what is currently used. No matter how promising a new treatment may appear during tests in a laboratory, it must go through clinical trials before its benefits and risks can really be known. and nor was the issue of substance abuse with pregabalin addressed.
Serious side effects were rare and were not different between those taking pregabalin and those taking placeboAn intervention that appears to be the same as that which is being assessed but does not have the active component. For example, a placebo could be a tablet made of sugar, compared with a tablet containing a medicine. tablets. However, less serious adverse events were common, particularly dizziness and sleepiness. Out of ten people taking pregabalin, six or seven will experience one or more adverse eventA harmful or abnormal outcome, for example death or vomiting, that occurs during or after the use of a drug or other intervention (e.g. surgery or exercise) but has not necessarily been caused by that intervention., though so will five or six out of ten people taking placeboAn intervention that appears to be the same as that which is being assessed but does not have the active component. For example, a placebo could be a tablet made of sugar, compared with a tablet containing a medicine..
Taking all the neuropathic pain conditions together, the results show a minimal increase in the rateThe speed or frequency of occurrence of an event, usually expressed with respect to time. For instance, a mortality rate might be the number of deaths per year, per 100,000 people. of adverse events at a daily dose of 600mg compared with 300mg, while in general the 150mg dose did not produce an excess of adverse events, except sleepiness in people with neuropathic pain following shingles.
The challenges for future research include providing information about who is likely to benefit and how the drug can be titrated to minimize adverse events.
Benefits and harms: a personal balancing act
Tim increased his pregabalin dose slowly, as advised, but it took some experimentation to get the dose ‘right’ for him. “At 200mg it got rid of the pain and allowed me to sleep at night, but I was falling asleep all the time during the day. Going down to 100mg I had pain in the night again. Settling at 150mg a day it’s debatable whether I’ve got the best or the worst of both worlds – I’m still sleepy during the day but I’m not too sleepy to work, and I still have some pain but it’s manageable.”
But that’s not all. Tim explains: “I’m enjoying the trippy dreams and I’m feeling more relaxed than I’ve felt in my life – which is really great! These side effects are benefits for me! What’s less good is that I sometimes lose bits of time; I can find it hard to remember what I did earlier in the day or the day before. Yet I am also thinking more clearly; when I’m working, being more relaxed seems to mean that my recall of systems and activities is sharper. How much is down to the pregabalin I don’t know – but don’t take it away!”
A complex reality
Of course, it’s complicated. Neuropathic pain is only one facet of Tim’s health profile and pregabalin one treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. among several. As he acknowledged, it’s not certain that everything he describes is down to the pregabalin. There’s guesswork, trialClinical trials are research studies involving people who use healthcare services. They often compare a new or different treatment with the best treatment currently available. This is to test whether the new or different treatment is safe, effective and any better than what is currently used. No matter how promising a new treatment may appear during tests in a laboratory, it must go through clinical trials before its benefits and risks can really be known. and error, in the mix, even with this new evidence providing more information than was previously available.
What matters to each of us differs and that could be crucial in decisions about treatments. A side effectAny unintended effect (e.g. dizziness or a headache) of an intervention such as a drug, surgery or exercise. that is intolerable to me might not bother you. It’s complicated. Once recommendations and decisions about a treatmentSomething done with the aim of improving health or relieving suffering. For example, medicines, surgery, psychological and physical therapies, diet and exercise changes. have been made, hopefully informed by the best available evidence, collecting a drug from the pharmacy may be just the beginning of a long and complex relationship, as we discover what it does for and to us, and how it fits (or doesn’t) in the day-to-day business of managing our health.
Join in the conversation on Twitter with @SarahChapman30 @CochraneUK @CochranePaPaS or leave a comment on the blog.
Reference: Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database of Systematic ReviewsIn systematic reviews we search for and summarize studies that answer a specific research question (e.g. is paracetamol effective and safe for treating back pain?). The studies are identified, assessed, and summarized by using a systematic and predefined approach. They inform recommendations for healthcare and research. 2019, Issue 1. Art. No.: CD007076. DOI: 10.1002/14651858.CD007076.pub3.
Sarah Chapman has nothing to disclose.
WHAT TO EXPECT WITH LYRICA
TERMS AND CONDITIONS
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Pregabalin Approved for Generalized Anxiety Disorder in Europe
NEW YORK, March 27 /PRNewswire-FirstCall/ — Pfizer Inc said today that the European Commission has approved Lyrica® (pregabalin) for the treatment of generalized anxiety disorder (GAD) in adults. In the European Union, it is estimated that nearly 12 million patients suffer from GAD on a yearly basis yet only one-third of these patients are properly diagnosed and even fewer received effective treatment.
Lyrica’s approval was based on five randomized double-blind clinical trials involving over 2,000 patients. Data from a combination of five placebo-controlled studies demonstrate that Lyrica provides rapid and sustained efficacy for the treatment of GAD. As early as the first week of treatment, Lyrica was shown to be significantly effective in providing relief of both emotional symptoms, such as depressive symptoms and panic, as well as physical symptoms, including headaches and muscle aches.
“GAD is much more than the normal anxiety people experience under times of stress. It is a chronic, debilitating illness that can greatly disrupt an individual’s daily life, yet the disorder is under-treated,” said Dr. Stuart Montgomery, Professor of Psychiatry, Imperial College School of Medicine, University of London. “Now that Lyrica is available, we have a new treatment option to help alleviate a broad range of emotional and physical symptoms of this prevalent condition.”
Generalized anxiety disorder, which affects an estimated five percent of people at some point in their lives, is a common and chronic psychiatric disorder characterized by excessive worry and tension about everyday routine life events and activities. Physical symptoms include poor sleep and fatigue, while the emotional symptoms include difficulty concentrating, irritability and restlessness. Generalized anxiety disorder occurs more frequently in patients with other chronic medical illnesses, especially those associated with pain conditions. The direct annual healthcare costs associated with GAD in Europe are approximately $1.5 billion.
“Lyrica represents an innovative treatment advance for patients suffering from generalized anxiety disorder,” said Dr. Joseph Feczko, president of Worldwide Development at Pfizer. “Early diagnosis and effective treatment is critical since prolonged anxiety increases impairment and worsens the outcome of co-existing illnesses.”
The most common adverse events reported by patients were dizziness and drowsiness. Most adverse events were mild to moderate in intensity and generally dose related.
In the United States, Lyrica® (pregabalin) C-V capsules are approved for the management of diabetic peripheral neuropathy, post herpetic neuralgia and adjunctive treatment of partial onset seizures. Lyrica is an alpha-2-delta ligand that is believed to work by calming hyper-excited neurons.
Developed by Pfizer, Lyrica has been approved for various neuropathic pain indications including peripheral neuropathic pain, diabetic and post herpetic neuropathic pain and adjunctive therapy for epilepsy in more than 60 countries outside of the United States.
Source: Pfizer Inc