Gabapentin And Pregabalin Lyrica Really Are A Danger To Your Neuropathic Health!

Today's post from pulsetoday.co.uk (see link below) is an impassioned plea from a home doctor who is seeing the consequences of long-term gabapentin and pregabalin (Lyrica) use in his surgery. Finally, a doctor who stands up to the hype that the pharmaceutical companies use to promote their drugs! Many, many neuropathy patients across the world have been prescribed either gabapentin or pregabalin for their nerve pain and other symptoms. This blog has long warned of the dangers of Lyrica (pregabalin) and advised patient to have serious discussions with their doctors if they are being prescribed these drugs. This article explains why and in terms you can't ignore. These drugs aren't the first and they won't be the last to display dangerous side effects years after the profit on them has been made. As Dr Spence says: "If it quacks like a duck and looks like a duck, then it’s a ducking duck"!

Gabapentinoids - the new diazepam?
Posted by: Dr Des Spence 9 September 2016

The establishment ignores GPs. It prefers the advice and glamour of ‘expert’ or media doctors. But the deference shown to the ‘expert’ is creating overtreatment, medicalisation and iatrogenic harm.

GPs have to ignore this advice. We won’t prescribe statins to everyone because it is irrational and stupid. We don’t accept that ‘pain is what the patient says it is’, because common sense dictates that it isn’t.

And we have seen the damage when experts have free rein. Diazepam was peddled as a safe and effective treatment for anxiety by companies and experts alike. When I started work in the early 1990s the consequence of this advice was evident everywhere. Herds of middle-aged patients zonked out and dependent on benzodiazepines. And benzodiazepines were being widely abused by a younger generation. My surgeries were spent dealing with drug-seeking behaviours, lies, confrontation, rebound agitation, insomnia and withdrawal seizures. It took the establishment decades to realise the harms we caused. Even today, we are still dealing with it.

GPs are first to notice the danger posed by psychoactive drugs. In the past five years my sensor has been off the scale with the gabapentinoids (gabapentin and pregabalin). Patients are seeking them using the crude acting skills that I used to witness with benzodiazepines: anger, tears and threats; constant requests for dose increases; stories of lost scripts; and a tag-team approach with friends who ‘corroborate’ stories.

If you google ‘gabapentinoids’, it is clear they are being widely abused. Large quantities are taken as single doses. Users describe them as the ‘ideal psychotropic drug’ with effects of ‘great euphoria’, ‘disassociation’ and an ‘opiate buzz’ as they boost the effects of these drugs.[1,2]

I wrote an article in the BMJ in 2013[3] highlighting these concerns. Since then, prescriptions have nearly doubled in three years to 10 million scripts and more than £300m in costs.[4] Such rapid increases are the signature of inappropriate prescribing and iatrogenic harm. Many practices started prescribing gabapentinoids on the back of specialist endorsement, despite the existence of effective and less harmful alternatives.[5,6] But requests from pain clinics and psychiatry come thick and fast. We decline many, then weather the storm of protest.

Do we have a problem with gabapentinoid abuse? If it quacks like a duck and looks like a duck, then it’s a ducking duck. Pregabalin is already a controlled medication in the US and there is debate about controls in the UK. The research base for the benefits of gabapentinoids is of short duration and in a small, defined population where as few as one in 10 benefits.[7] We need to change our prescribing policy now and limit the use of gabapentinoids.[2]

We know the pattern: GPs will be blamed even if we just follow orders. I get tired that no one listens to generalists. This is déjà vu. Do we want another benzodiazepines disaster?

Dr Des Spence is a GP in Maryhill, Glasgow, and a tutor at the University of Glasgow

References Schifano F, D’Offizi S, et al. Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychother Psychosom 2011;80:118-22
Advice for prescribers on the risk of the misuse of pregabalin and gabapentin. Public Health England, 2014
Spence D. Bad medicine: gabapentin and pregabalin BMJ 2013; 347 08 November 2013
NHS Prescription Cost Analysis data. NHS Business Services Authority, 2016
Wiffen P, Derry S, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews Cochrane Database Syst Rev 11 November 2013; (11):CD010567
Moore R, Derry S, et al. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012 Dec 12;12:CD008242
Advice on the anticonvulsant drugs pregabalin and gabapentin. Advisory Council on the Misuse of Drugs, 2106 

http://www.pulsetoday.co.uk/views/blogs/gabapentinoids-the-new-diazepam/20032721.blog

NICE Judgement On Pregabalin Lyrica

As part of the ongoing argument about the efficiency of pregabalin (Lyrica) for treating neuropathic pain symptoms, today's post from pulsetoday.co.uk  (see link below) examines the decision by NICE (the British National Institute for Health and Care) to backtrack on its plans to relegate pregabalin to a second drug of choice (behind gabapentin) in the treatment of neuropathic pain. Apart from the fact that gabapentin is cheaper than pregabalin, the ongoing controversies surrounding pregabalin (effectiveness and side effects issues) have led more and more doctors to prescribe gabapentin first. People with HIV and/or diabetes plus neuropathy should also be aware that Pfizer (the makers) have withdrawn their support (May 2012) for their own drug relating to those diseases because it has never been proved to work effectively for those groups and the law suits thanks to unpleasant side effects have brought yet more discredit on pregabalin as a treatment option. The best advice is to talk it over with your doctor or specialist but you may need to take further evidence with you if you're worried about taking pregabalin (Lyrica) because many doctors are still unaware of Pfizer's own policy. Many more articles about this drug can be found in the alphabetical list to the right of this blog.

NICE backs down on pregabalin restriction for neuropathic pain
22 November 2013 | By Caroline Price

NICE has back-tracked on controversial plans to demote pregabalin to second-line use after gabapentin in the management of neuropathic pain, it revealed in updated guidance released this week.

GPs can now offer either pregabalin, gabapentin, amitriptyline or duloxetine as initial treatment in patients with any type of neuropathic pain, with the exception of trigeminal neuralgia for which carbamazepine is the recommended initial treatment.

The decision marks an apparent climb-down by the regulator after it previously announced plans to switch pregabalin for gabapentin as a recommended first-line treatment on the grounds of cost.

NICE initially recommended amitriptyline or pregabalin first-line in treatment options in its first-ever guidance on pharmacological management of neuropathic pain published in 2010, with duloxetine recommended first-line for patients with painful diabetic neuropathy.

But within 18 months it announced a review of the decision on pregabalin, because of cost concerns – and proposed swapping gabapentin as an alternative first-line drug of choice.

However, the newly published final guidance reverses that proposal and leaves the choice down to GPs, with advice on what to try if the initial treatment is ineffective or not tolerated.

Dr Ollie Hart, a GPSI in pain in Sheffield, said the guidance was welcome and would reflect common practice, although he said most GPs would choose gabapentin before pregabalin because of the cost.

He told Pulse: ‘It reflects common practice where often clinicians rotate medications in a trial of “n=1” with the individual patient, with regular review of effects.

‘Most GPs would (and I would recommend) using gabapentin before pregabalin. Cost/value issue make this the sensible decision for most.’

Dr Hart said more detail would have been useful on how long initial treatments should be tried and it was disappointing the off-licence status of cheaper drugs has been highlighted in the guidance.

He said: ‘It would have been more helpful if they had indicated time frames for trailing meds - in reality I often allow two-to-four weeks for evidence of benefit or not.

‘It is a shame that they have chosen to highlight the off-licence aspects of some of the medications- amitriptyline for example has a long a well evidenced history of use in neuropathic pain. We are working in an NHS system where value based decisions have to be made,’ Dr Hart added.

http://www.pulsetoday.co.uk/clinical/therapy-areas/pain-relief/nice-backs-down-on-pregabalin-restriction-for-neuropathic-pain/20005139.article#.UsaDDbRhOSo

Duloxetine Cymbalta or Pregabalin Lyrica or Both

Monotherapies or combination therapies to treat neuropathy (one or more drug at the same time), is a dilemma that both doctors and drug companies are tackling at the moment. As always, evidence-based research is essential and in today's post about Cymbalta (Duloxetine) and Lyrica (Pregabalin), the jury seems to still be out regarding which treatment is best. The article comes from Diabetesincontrol.com (see link below) and is interesting for neuropathy sufferers for whom the tricyclical antidepressants have failed to make any difference. The problem is that both Cymbalta (Duloxetine) and Lyrica (Pregabalin), can bring various unpleasant side effects with them. Patients need to take that into consideration before starting these drugs. Doctors frequently play down the side effects because they can be so subjective but people have a right to know what's potentially in store for them. Neuropathy is bad enough without being surprised by new side effects from the drugs that are meant to help.

New Choices for Neuropathy Treatment

Researchers suggested that, switching to duloxetine (Cymbalta) or pregabalin (Lyrica) can produce pain relief for patients with diabetic neuropathy who stop responding to gabapentin (Neurontin)....

Robert Tanenberg, MD, of East Carolina University in Greenville, N.C., reported at the American Academy of Pain Medicine that, adding duloxetine to gabapentin also produced similar pain relief as monotherapy,

On the 11-point Likert pain severity scale, 12-week treatment with duloxetine monotherapy reduced severity 2.62 points, which proved to be noninferior to a 2.12-point reduction with pregabalin. It was also noninferior to the combination of duloxetine and gabapentin, which registered a 2.39-point decline in pain severity.

Tanenberg said that five different analyses of the results, including intention-to-treat and per protocol methodology came up with noninferiority conclusion for both the primary and secondary endpoints.

Tanenberg mentioned that, "It makes more sense to substitute a monotherapy approach rather than adding another drug to treatment."

At his poster presentation he said that, "Duloxetine and pregabalin are both good drugs for reducing neuropathic pain in these patients who are no longer responding to gabapentin."

"I'm not surprised at these results," said Mike W. Hooten, MD, of the Mayo Clinic in Rochester, Minn. "The efficacy of all these drugs is similar in patients with peripheral neuropathy."

Hooten, who did not participate in the study, noted that, "The results of the study show that we have additional options for our patients."

"Historically," Tanenberg reported, "diabetic peripheral neuropathy has been treated with tricyclic antidepressants, certain anticonvulsants such as gabapentin and opioid analgesics. However, the use of these agents is often limited by lack of efficacy or significant side effects."

"Pain due to diabetic neuropathy is commonly experienced in the feet or ankles, and if inadequately treated, it is often associated with mood and sleep disturbances."

Tanenberg said doctors should select those options on the basis of the adverse event profile of the drugs and how individual patients are likely to respond to therapy.

For example, he noted that weight increased with pregabalin treatment and decreased with duloxetine and the duloxetine-gabapentin combination. Nausea and insomnia were seen less often with pregabalin than with the duloxetine treatments. Peripheral edema, however, was more common with pregabalin.

In the open-label, randomized study, Tanenberg and his team enrolled 134 patients to receive pregabalin, 135 to receive the combination of duloxetine and gabapentin, and 138 patients to receive duloxetine. There were 96 patients on pregabalin who completed the 12-week study compared with 96 patients on the combination treatment and 87 patients taking duloxetine.

Tanenberg acknowledged that the open-label nature of the study limits generalization of the results. "The lack of blinding may have influenced the evaluation of efficacy and adverse events for both the patients and the investigators," he said.

And "without a gabapentin monotherapy control group, a conclusion drawn from the differences observed between duloxetine monotherapy and duloxetine-gabapentin must be viewed with caution," Tanenberg said.

He also noted that the 12-week length of the study makes it unable to address long-term outcomes.

The patients in the study had a mean age of about 61; about 80% were Caucasian; about 60% were men. Nine out of 10 of the patients were Type 2 diabetes patients. They had been diagnosed with diabetic peripheral neuropathy for least four years. At baseline, the average pain severity score was about 5.8.

Practice Pearls:
Note that in a randomized open label study, sponsored by the makers of duloxetine, duloxetine and pregabalin were equivalent in reducing pain in patients who no longer respond to gabapentin for peripheral diabetic neuropathy.
Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Tanenberg R, et al "An open-label, randomized comparison of duloxetine, pregabalin, and the combination of duloxetine and gabapentin among patients with inadequate response to gabapentin for the management of diabetic peripheral neuropathic pain" AAPM 2011; Abstract 263

http://www.diabetesincontrol.com/articles/diabetes-news/10735-new-choices-for-neuropathy-treatment

Consequences of Pfizers Withdrawal Of Lyrica For Types Of Neuropathy

 Many people were disappointed when in may 2012, Pfizer withdrew approval for its own drug Lyrica (pregabalin) for the treatment of diabetes and HIV-related neuropathy. Just as many people weren't surprised, considering the number of side effects and court cases that Pfizer had to settle. Many doctors have still not yet caught up with the news and are still prescribing Lyrica for those two forms of neuropathy. It may be up to you to enter into a discussion with your doctor about the implications. The second half of the article is not so much neuropathy-related but is intersting in that it shows how the drug companies operate and what their bottom lines sometimes are.

 

Pfizer Could Plummet Without Lipitor Replacement
May 11, 2012 by Mel Daris

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours.

 Pfizer (PFE) is facing several problems at the moment. First, its patent on Lipitor is expiring. Second, it terminated the latest trial for Lyrica. Lyrica, which is intended to treat painful diabetic peripheral neuropathy, failed in its Phase III study. Lyrica was supposed to be the replacement drug for Lipitor, in terms of revenue for the company.

 Lyrica was meant to be a drug that would treat neuropathic pain in patients with HIV, which is characterized by a form of nerve damage that results in burning pain usually beginning in the feet. The termination of the trial was the result of a decision made by the external Data Monitoring Committee (E-DMC) that performed an interim study of the trial. At this stage, it appears that the trial was not stopped for safety reasons.

 The trial followed "A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Trial of Pregabalin Versus Placebo in the Treatment of Neuropathic Pain Associated with HIV Neuropathy" format. This basically means that half of the subjects were given Lyrica and the other half were given a placebo without knowing what they were receiving. The reason that the E-DMC elected to stop the trial was because there were virtually no differences in the results that were experienced by the real test subjects as opposed to those who were only taking the placebo drug.

 As there are no treatments at present to deal with this form of neuropathic pain that is so closely associated with HIV, Pfizer has really missed its chance to make an impact on the pharmaceutical arena and will have to start looking elsewhere for success. Lyrica is approved in many countries as well as in the U.S., but not for the treatment of neuropathic pain in HIV sufferers.

 The company also performed a "Multicenter, Double-Blind, Randomized Withdrawal Efficacy and Safety Study of Pregabalin in the Treatment of Patients with Inadequately Treated Painful Diabetic Peripheral Neuropathy" in order to see if the same drug, Lyrica, would be effective in treating the highly painful neuropathy experienced by diabetics. However, like with the trial to test the use of Lyrica in neuropathy associated with HIV, the results were not statistically significant.

 The bottom line is that Lyrica has fallen short of expectations in no less than two pain studies. The company, which is trying so desperately to find a way to recover from the losses it's experiencing due to the expiration of several patents, now has to deal with two more failures. Lyrica would have provided the company with new growth avenues for the drug, which could have potentially combated the losses that it is experiencing due to the expiration of its patent on Lipitor. As things stand, the company will have to consider taking another direction. Despite this, Lyrica sales did increase by 16% in the first quarter, although this is not enough to account for the losses involved in no longer having the Lipitor patent.

 Pfizer now will need to adapt in order to remain as profitable as possible now that it has lost the valuable patents for its main drugs. Lipitor, the company's most profitable drug and the best selling drug in pharmaceutical history, is now no longer the favorite as cheaper patents are introduced to the market. Clearly the company needs to do something in order to counteract this problem.

 Pfizer's response to the situation is seemingly to downsize. The company is attempting to shed unnecessary expenses by selling such things as its baby formula company to companies like Nestlé. It also plans to sell its animal medicine business next year. In addition, Pfizer is choosing to slash its budget and focus only on those areas of healthcare science that show the most promise, namely Alzheimer's and cancer treatments. Stockholders can only hope that this attempt to reinvent itself will be what puts Pfizer back in the game.

 An examination of Pfizer's competitors shows that the competition is quite strong. Abbott (ABT), for example, recently bought a potential kidney medication for a $110 million from a privately held Danish company, Action Pharma. The main purpose of the drug is to protect patients who are undergoing cardiac surgery from suffering severe kidney injuries that can arise from a lack of blood flow during surgery.

 Merck (MRK) has recently teamed up with Trevena in a project aimed at "exploiting the latter's technologies to screen for biased ligands against a specified receptor." The idea is to develop drugs that increase specificity, as well as enhance efficacy and reduce side effects. Should the trials that are currently under way be successful, it will mean good things for both Merck and Trevena, marking both as good horses to bet on.

 Novartis (NVS) is not having as much luck. Recently it was discovered that a cheaper drug than the Lucentis drug marketed by Novartis is just as effective at combating age-related macular degeneration. The cheaper drug, Avastin, is not yet licensed. Doctors nevertheless are increasingly prescribing the cheaper drug over the more expensive one in an attempt to make the treatment for age-related macular degeneration more affordable for the many patients suffering from it. Novartis will need to come up with an answer for the sloping sales.

 Sanofi (SNY) is maintaining a consistently pessimistic outlook for the coming year even though it experienced an increase in profits in the first quarter. The company expects that its profits will continue to slide over the coming months. Like Pfizer, the company is suffering from the fact that its best-selling medications are being undermined by cheaper generics, and this is causing sales to decrease significantly with an unfortunate backlash for the company.

 There's a clear split, currently, with the top drug companies. Pfizer, consistently a company at the top tier of the industry, faces the possibility of being on the losing side right now. It needs, more than ever, to respond to the loss of Lipitor revenue. If it can't, it may be doomed until it comes up with something -- and that timeline could be very long indeed.

http://seekingalpha.com/article/582811-pfizer-could-plummet-without-lipitor-replacement

Duloxetine Cymbalta Vs Pregabalin Lyrica For Neuropathy

Today's post from diabetes in control.com (see link below) compares and contrasts two more widely prescribed drugs for neuropathy - the antidepressant Duloxetine (Cymbalta) and the anticonvulsant  Pregabalin (Lyrica). However, before you read on, please be aware that the makers of Lyrica (pregabalin) Pfizer, withdrew their support for its use with both HIV and diabetes-related neuropathy in May 2012; officially due to its ineffectiveness. If your doctor wishes to prescribe the drug to you, it may well be worth your while bringing this to his or her attention and asking whether it truly is the best option for you. That all said, both drugs have been widely used to reduce neuropathic pain for years now but with very mixed results. The side effects can play a significant role  as to whether the drugs are acceptable for patients and should not be underestimated. You can read more posts about these drugs in the alphabetical list to the right of the blog, or by using the search button. This particular article comes to the conclusion that Duloxetine (Cymbalta) is more effective that Pregabalin (lyrica), for the reasons shown below.

Duloxetine Beats Pregabalin for Diabetic Neuropathy

This article originally posted 12 October, 2012 and appeared in Medication, Neuropathy, Issue 647

The largest trial ever conducted for the treatment of diabetic peripheral neuropathic pain (DPNP) has shown which treatment works best....

The study showed that initial treatment with duloxetine (widely known as Cymbalta) provides better analgesia than pregabalin in treatment-resistant patients.

Combination therapy with the two drugs, although not superior to high-dose monotherapy, appeared to be safe, effective, and well tolerated.

Stefan Wilhelm, MD, senior medical advisor at Lilly Deutschland in Bad Homburg, Germany, presented the results of the Combination vs Monotherapy of Pregabalin and Duloxetine in Diabetic Neuropathy (COMBO-DN) study at the European Association for the Study of Diabetes 48th Annual Meeting. The 2 drugs are the only ones currently approved in the United States and Europe for the treatment of DPNP, and no previous large head-to-head or combination treatment trial has been conducted.

The primary objective of the double-blind randomized parallel-group study was to evaluate the drugs in combination in patients who had not responded to standard doses of each drug alone, and to evaluate each drug as monotherapy for the initial treatment of pain.

Study participants were men and women 18 years and older who had daily bilateral peripheral neuropathic pain for more than 3 months. Initial pain scores had to be at least 3 on the 10-point Michigan Neuropathy Screening Instrument and at least 4 on the Brief Pain Inventory Modified Short Form (BPI-MSF) 24-hour average pain severity scale.

Participants underwent a 1- to 2-week screening and washout period; they could not have been on either study drug for more than 15 days before the washout period and had to have stable glycated hemoglobin not greater than 12% at the beginning of the washout period.

In the initial period, patients were divided into 2 groups: 401 patients received a half dose of duloxetine for 1 week followed by a full dose of duloxetine (60 mg) for 8 weeks, and 403 patients received a half dose of pregabalin for 1 week followed by a full dose of pregabalin (300 mg) for 7 weeks.

The 339 patients who did not respond to therapy in the initial period entered the intensive period. In this phase, the dose of monotherapy was doubled or the other drug was added at its full dose for an additional 7 weeks, followed by a 2-week tapering phase. This phase was designed to investigate whether combination or high-dose therapy was a better option for patients with incomplete pain relief.

The mean age in each group was 61 years, and the groups were well matched for sex, weight, race, time since diabetes diagnosis (median, 11 years), time since neuropathy diagnosis, and time since neuropathic pain onset (median, 2 years). Two thirds of the patients in each group had not previously received DPNP therapy.

During the initial period, duloxetine was associated with significantly better pain relief at week 4 (P = .007) and at week 8 (P < .001). At week 8, the BPI-MSF score had decreased by about 2.3 points in the duloxetine group and by about 1.6 points in the pregabalin group.

During the initial period, more patients in the duloxetine group than in the pregabalin group experienced a pain reduction of at least 30% (52.0% vs 36.9%; P ≤ .001), at least 50% (40.3% vs 27.8%; P < .001), and at least 2 points (57.1% vs 45.7%; P = .002).

"For nonresponders, after 8 weeks of treatment in the intensive period, it makes no difference whether you combine these 2 drugs at the standard doses or whether you give high doses in both groups," Dr. Wilhelm reported. "There was no significant difference at the end of the intensive treatment phase," he noted.

In the initial period, a subgroup analysis showed that all outcomes favored duloxetine. In the intensive period, all outcomes trended toward favoring combination therapy, but no outcome was statistically significant.

The drugs were similar in safety and tolerability. In the initial period, about 56% of patients experienced a treatment-emergent adverse event, but only about 12% discontinued either drug. The main treatment-emergent adverse events were dizziness, somnolence, and nausea. Serious adverse events affected about 3% of patients on either drug.

Session moderator Rayaz Malik, MD, PhD, professor of medicine at the University of Manchester in the United Kingdom, succinctly summarized the trial results.

"This is the largest trial in painful diabetic neuropathy that's ever been done.... Duloxetine was better, with no difference in side effects. When the combination was tried, although overall there was no difference, you could see that there were clearly trends," he explained. "From a clinical perspective, having 2 therapies gives me an option in terms of pushing up the dose to the maximum or giving the combination," he noted.

This study design, in which only treatment-resistant patients were included, leaves an unanswered question. Dr. Malik speculated that if other patients had been included, there might have been a difference.

For initial therapy in treatment-resistant patients, the choice is clear, he said. "For me, it would make me think twice if I have a choice between pregabalin and duloxetine, given that duloxetine has performed better," Dr. Malik said. Therefore, clinicians should feel comfortable acting on these results. "They have to. There are not going to be any more studies of combinations or single agents," he said.

European Association for the Study of Diabetes (EASD) 48th Annual Meeting: Abstract 48. Presented October 2, 2012.

http://www.diabetesincontrol.com/index.php?option=com_content&task=view&id=13657&Itemid=8

The Scandal Of Lyrica Gabapentin And Cymbalta For Neuropathy Patients

Today's post from ti.ubc.ca (see link below) reinforces the latest evidence that shows that Lyrica, gabapentin and Cymbalta (pregabalin, gabapentin and duloxetine) have very little effect on patients' nerve pain when compared to placebos. It's enough to make you hopping mad (if hopping weren't so painful!) when you realise that very successful pharmaceutical company advertising campaigns have promoted these drugs to the top of doctors' lists when treating neuropathic pain. The patient clearly comes last in the equation and for years now people have been exposed to these drugs and their side-effects without any proven benefits. Time to have a serious discussion with your doctor or specialist, wherein you can ask them how they can justify their prescriptions. The idea that doctors turned to these drugs to prevent a rapid progression towards opioids is just to weak for words.

Benefits and harms of drugs for “neuropathic” pain 
January 19, 2016 Therapeutics  Cochrane reviews

Chronic pain (at times presumed to be “neuropathic” in origin) is a common problem in clinical practice. It is now well recognized that the results of drug treatment are more often disappointing than not.1 Despite this, from 2005-2014 the number of British Columbians prescribed gabapentin increased 1.8 fold, pregabalin 17 fold, and duloxetine 3.6 fold (from 2008). Use of venlafaxine (mostly for depression/anxiety) has remained relatively stable.

Most gabapentin, pregabalin, and duloxetine use in B.C. is for chronic pain, driven partly by concern about problems with long-term opioid therapy. For the same reason, tricyclic antidepressants (amitriptyline, nortriptyline, imipramine, desipramine) are often prescribed for “neuropathic” pain.

In 2009 Therapeutics Letter 75 on gabapentin2 concluded:
Gabapentin reduces neuropathic pain by < 1 point on a 0-10 point scale and benefits about 15% of carefully selected patients (NNT=6-8).
A similar proportion of people suffer harm (NNH=8).
A test of benefit/harm can be made after 1-2 days at a low dose (100-900 mg/day).
Benefit is unlikely to increase with higher doses or longer treatment.

This Letter updates information on gabapentin and critically appraises randomized clinical trials (RCT) assessing the benefits and harms of three other drugs promoted for neuropathic pain: pregabalin, duloxetine, and venlafaxine. It is based primarily on 4 Cochrane reviews.3-6 Like many systematic reviews, these either did not assess risk of bias, or did not fully reflect the implications of the risk of bias in their conclusions. We attempt to demonstrate how appreciation of the biases in RCTs can be incorporated into the conclusions of systematic reviews.

Benefits

Although all pain metrics have limitations7 a 50% or greater reduction from a baseline pain score has been promoted as a more clinically relevant outcome for “neuropathic” pain because it correlates with improvements in comorbidity, function and quality of life.4 Using this outcome across all 4 Cochrane reviews, the mean number of people who must be treated for one to achieve a ≥ 50% reduction in pain (NNT) compared to placebo is about 6. This calculation is based on all doses that were statistically significantly superior to placebo. The evidence is weakest for venlafaxine, but even for gabapentin, pregabalin, and duloxetine, this NNT is likely very optimistic, as we judged the included RCTs to have a high risk of bias.

The greatest potential bias comes from the likelihood that patients and investigators were unblinded by observing drug adverse effects such as somnolence. Loss of blinding has been shown to be associated with a 68% exaggeration of relative benefits for subjective outcomes such as pain.8 In addition almost all RCTs included in the Cochrane reviews were funded by drug manufacturers. A separate Cochrane review demonstrated that industry funded studies lead to “more favourable results and conclusions” than non industry funded studies.9 Accounting for these biases, we suspect the real NNT for benefit from these drugs is at least 10.

An alternative measure of meaningful benefit is the patient’s reported global impression of change (PGIC). PGIC was not reported in any venlafaxine RCT3 and no meaningful difference was found for duloxetine.4 For gabapentin and pregabalin, the estimated NNT for “much or very much improved” PGIC ranges from 6-10.5,6 Like the ≥50% pain score reduction, this is probably overly optimistic.

The evidence of benefit for tricyclic antidepressants for neuropathic pain is weaker and it is not possible to estimate a meaningful NNT.10-13
 
Harms

Withdrawals due to adverse effects compared with placebo were higher with gabapentin, pregabalin, duloxetine and venlafaxine.3-6 Approximately 80% of people receiving these drugs experienced at least one adverse effect. The most common were somnolence, dizziness, and nausea. Anticholinergic effects, such as dry mouth and constipation, were common with duloxetine. The rate of adverse effects reported in Cochrane reviews almost certainly underestimate the real world rates because patients at higher risk (e.g. from impaired kidney function, alcohol use, or with other morbidities) are excluded from RCTs. Furthermore, official product monographs for these drugs report higher rates of adverse effects than do the Cochrane reviews.

The most common adverse effects reported for the tricyclic antidepressants were dry mouth, sedation and constipation.10-13 Likewise official monographs provide a better and higher estimate of the incidence of harms than the systematic reviews. 

To whom do the Cochrane reviews apply?

Patients averaged 50 years of age, had moderate levels of neuropathic pain, and were free of medical conditions other than those being studied (diabetes, fibromyalgia, or post-herpetic neuralgia). RCTs varied with respect to allowed use of other analgesics from acetaminophen only to the use of multiple analgesics including opioids. 

How soon is pain reduced?

In the majority of trials pain reduction compared with placebo was demonstrable within the first week. Very little additional pain reduction occurred after the second week.

Is there evidence that increasing dose improves response?

For gabapentin, pregabalin, duloxetine and venlafaxine, RCTs demonstrated little or no benefit from doses higher than the lowest dose that was superior to placebo.3-6
 
Clinical implications

Evidence from 8 Cochrane reviews should temper expectations regarding the likelihood and magnitude of pain relief from gabapentin, pregabalin, duloxetine, venlafaxine, amitriptyline, nortriptyline, imipramine or desipramine. When initiating a therapeutic trial with one of these drugs in a patient, it is reasonable to start at the lowest recommended dose and assess the patient for benefit and harm at 1 week. If benefit harm ratio is unacceptable, consider stopping the drug. If insufficient but partial pain relief is achieved, increase the dose and reassess within 1 week. If functionally meaningful benefit is still absent, stop the drug and try something else. For patients who achieve clinically meaningful analgesia, use the lowest individualized effective dose to minimize adverse effects. Reassess regularly (e.g. every 2 weeks), as most patients treated with placebo also improve over time.

Conclusions 
 
The evidence base for drug treatment of neuropathic pain is weak, due to the small magnitude of clinically meaningful effects and the high risk of bias in the RCTs.

Probably less than 1 in 10 patients achieve a meaningful reduction in pain.
Most patients experience some adverse side effects like somnolence, dizziness, nausea, dry mouth and constipation.
To identify patients who respond, a therapeutic trial with early assessment is essential. Reassessment of drug utility is needed to detect people with spontaneous remission or placebo response.
Higher doses are unlikely to achieve greater pain reduction, but are more likely to cause harm.

References 
 
Moore A, Derry S, Eccleston C, Kalso E. Expect analgesic failure; pursue analgesic success. BMJ. 346:f2690, 2013.
Therapeutics Initiative. Gabapentin for pain. New evidence from hidden data. Therapeutics Letter. 2009; 75:1-2.
Gallagher HC, Gallagher RM, Butler M, et al. Venlafaxine for neuropathic pain in adults. Cochrane Database of Systematic Reviews, 2015 Issue 8. Art. No.: CD011091. DOI: 10.1002/14651858. CD011091.pub2.
Lunn MPT, Hughes RAC, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD007115. DOI: 10.1002/14651858.CD007115.pub3.
Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. NO.: CD007076. DOI: 10.1002/14651858.CD007076.pub2.
Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews, 2014, Issue 4. Art. No.: CD007938. DOI: 10.1002/14651858.CD007938.pub3.
Ballantyne JC, Sullivan MD. Intensity of Chronic Pain – The Wrong Metric? N Engl J Med 2015;373(22): 2098-9.
Hrobjartsson A, Thomsen AS, Emanuelsson F, et al. Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. CMAJ 2013 Mar 5;185(4):E201-11.
Lundh A, Sismondo S, Lexchin J, et al. Industry sponsorship and research outcome. Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: MR000033. DOI:10.1002/14651858.MR000033.pub2.
Moore RA, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain in adults. Cochrane Database of Systematic Reviews 2015, Issue 7. Art. No.: CD008242. DOI: 10.1002/14651858.CD008242.pub3.
Derry S, Wiffen PJ, Aldington D, Moore RA. Nortriptyline for neuropathic pain in adults. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD011209. DOI: 10.1002/14651858.CD011209.pub2.
Hearn L, Moore RA, Derry S, et al. Desipramine for neuropathic pain in adults. Cochrane Database of Systematic Reviews 2014, Issue 9. Art. No.: CD011003. DOI: 10.1002/14651858.CD011003.pub2.
Hearn L, Derry S, Phillips T, et al. Imipramine for neuropathic pain in adults. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD010769. DOI: 10.1002/14651858.CD010769.pub2.
The draft of this Therapeutics Letter was submitted for review to 60 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.
The Therapeutics Initiative is funded by the BC Ministry of Health through a grant to the University of BC. The Therapeutics Initiative provides evidence-based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies .

http://www.ti.ubc.ca/2016/01/19/96-benefits-and-harms-of-drugs-for-neuropathic-pain/