Margaret McCartney: Second use patents—why do we have to prescribe branded Lyrica for pain?

Response to “No Holds Barred”, by Margaret McCartney, BMJ 6 June 2015

With regard to the recent direction from a number of NHS health authorities that pregabalin prescriptions for chronic pain should be written only for the proprietary brand name of the Pfizer brand of this chemical, it should be noted that a neuropathic aetiology has not been established in a significant proportion of cases in which pregabalin is prescribed for help with pain symptoms*. Pregabalin is a popular drug, with a widespread patient following (and an increasingly evident abuse potential, like some other drug classes which share its anxiolytic effect). It is likely that in many cases a patient’s report of improvement in pain symptoms while taking pregabalin is related to this anxiolytic effect, rather than to a specific effect on the pain pathway.

Whether the UK courts would punish a doctor who wrote a prescription for a patient with pain symptoms without using the Pfizer brand name has yet to be tested. One would feel that the route of such a case to court would not be straightforward: after all, there would seem to be no plausible suggestion that a patient would suffer harm from using a good-quality generic pregabalin in place of the Pfizer brand. (This lack of potential for harm would also seem to exclude GMC intervention.) It is also unlikely that the patient’s clinical details would be available to the court; commercial reasons should not be accepted as grounds for abrogating medical confidentiality (and, hopefully, pharmacists would also be covered by this protection.) It also seems unlikely that individual NHS doctors can be found to owe a duty of care to the Pfizer company.

Obviously there is likely to be concern among front-line doctors that the recent direction from NHS health authorities represents “regulatory capture”. It is of interest that that the common sense of Sir Bruce Keogh's initial response was evident in his 10 February 2015 letter to the court dealing with Warner-Lambert's application to restrain competing manufacturers from supplying pregabalin for neuropathic pain : however , that common sense position was then abandoned by the time of the NHS directions issued the following month.

These directions go further than is reasonable: trying to restrict prescribing of pregabalin to the Pfizer brand name in cases where there is a definite positive diagnosis of neuropathic pain might have been understandable ( though reprehensible) in view of the Pfizer claim to a continuing patent for this indication, but trying to make sure that all prescribing of pregabalin for pain must be by Pfizer brand name until March 2017 seems deeply irresponsible and wasteful of the nation's resources.

Ref: Giladi et Al, Current Medical Research and Opinion July 2015, vol 31, 1403-1411 (abstract seen); three-quarters of a Canadian series of 355 patients taking pregabalin for chronic pain were doing so for “off-label” reasons

Dear Editors

I note Dr LS Lewis' (not LL Sam, my error) reply to my recent rapid response.

Readers of course would realise that my 2 main assertions from my original rapid response, as always, is that:

1. There are more drugs than just Lyrica branded pregabalin licensed for use for neuropathic pain in UK, and with no evidence pregabalin is any better than Amitriptyline (unlicensed for neuropathic pain in UK) or Gabapentin (licensed for neuropathic pain in UK), why are we focussed on Lyrica and pretending that it is the only drug available for treatment?

2. There are surprisingly more people than expected being put on Lyrica for neuropathic pain even though the patients have no pain that can be considered neuropathic; the perceived "need" for Lyrica prescribing may be more than the actual efficacy of their use for the wrong indication.

Dr Lewis suggest that NICE may be able to unravel the licensing blocks but I would suggest they have already stated their recommendation!

For those who are outside UK the following are from the latest revised April 2015 NICE Clinical Knowledge Summaries: Neuropathic pain — pharmacological management. The pharmacological management of neuropathic pain in adults in non-specialist settings from http://cks.nice.org.uk/neuropathic-pain-drug-treatment

"The use of amitriptyline for the management of neuropathic pain is off-label. However, it is widely used for this indication in current practice. This is supported by the National Institute for Health and Clinical Excellence"

"Pregabalin is licensed for the treatment of peripheral and central neuropathic pain in adults. The National Institute for Health and Care Excellence recommends pregabalin as a first-line treatment option for adults with all neuropathic pain (except trigeminal neuralgia)"

"Gabapentin is licensed for the treatment of peripheral neuropathic pain such as painful diabetic neuropathy and post-herpetic neuralgia in adults. The National Institute for Health and Care Excellence recommends gabapentin as a first-line treatment option for adults with all neuropathic pain (except trigeminal neuralgia)"

"Duloxetine is licensed for the treatment of diabetic peripheral neuropathic pain. However, the National Institute for Health and Care Excellence recommends duloxetine as a first-line treatment option for adults with all neuropathic pain (except trigeminal neuralgia)"

"Capsaicin 0.075% cream (Axsain®) is licensed for the symptomatic relief of postherpetic neuralgia after open skin lesions have healed, and for the symptomatic relief of painful diabetic neuropathy (only under the direct supervision of a hospital consultant who has access to specialist resources). The National Institute for Health and Care Excellence recommends capsaicin cream for people with localized neuropathic pain who wish to avoid, or cannot tolerate, oral treatments"

"Although not specifically licensed for the neuropathic pain, tramadol is licensed for the treatment of moderate to severe pain. The National Institute for Health and Care Excellence (NICE) recommends tramadol for people with neuropathic pain (except trigeminal neuralgia), only if acute rescue therapy is needed"

At the end of the day I support the concept that drugs should be allowed to prescribed and dispense for off-label indication and licencing blocks may be in fact unethical by the consumption of financial resources more than necessary, thus leaving less resources for use for other causes. I suspect Dr LS Lewis may subscribe to this as well.

Unfortunately it requires a formal legal ruling to overturn these licensing restrictions (which is commercially motivated, by itself not necessarily a 'bad" thing, but certainly leads to increased distrust among the community regarding big pharma).

Dear Editors

I noted Dr LL Sam's rapid response stating "European Law seems to require UK doctors to prescribe only LYRICA for neuropathic pain, since it is the only agent licensed for the indication."

I stand corrected with thanks if that is the case.

I take it then that the information in Box 2 in this article (as previously referenced as ref 1 in my rapid response) http://www.bmj.com/content/347/bmj.f7339 is outdated then?

Similarly it is possible I have misread the NICE website information last updated in April 2015. http://cks.nice.org.uk/neuropathic-pain-drug-treatment
(access limited to within UK)

Fellow readers, I unreservedly apologise if I did unintentionally used outdated information to mislead you.

Again a gentle reminder, try gabapentin for neuropathic pain if the licence for this indication haven't been revoked since April 2015.

You know how it goes with skinning the cat...... if you got the licence for it!

References:

1. Kalso E, Aldington DJ. Drugs for neuropathic pain. BMJ 2013;347:f7339 doi: 10.1136/bmj.f7339

Dear Editors

I am entering into this discussion about Lyrica and the second use patent on neuropathic pain as I am surprised at the nature of some assertions made, as well as the lack of evaluation of drug prescribing behaviour (an apparent irony I am aware of given my public stance on other issues but not in my view contradictory)

Firstly it is important to establish that current definition of neuropathic pain does include radicular pain of which sciatica is considered as a subtype of. However I do agree with some readers that the mainstay of treatment of acute sciatica should be supportive non-pharmaceutical measures facilitated by limited and short-term use of analgesics and NSAIDs to aid mobilisation. Chronic recalcitrant sciatica may be managed pharmacologically with various neuromodulating agents such as antidepressants and antiepileptics.

Many guidelines in UK and Australia, including government-funded organisations such as the Australian NPS MedicineWise recommend the use of TCA (Tricyclics Antidepressants) such as amitriptyline for use as first line drugs, and gabapentin (and later pregabalin) for those cases refractory to 'standard' treatment. In UK duloxetine, carbamazepine and other drugs are also recommended, some as first line.

However the Australian PBAC (Pharmaceutical Benefits Advisory Committee) inadvertently assisted the rapid uptake of pregabalin to manage neuropathic pain, since pregabalin is the only approved drug for use under the General PBS subsidy program albeit the "refractory" clause (Gabapentin is only subsidised under Repatriation PBS or RPBS). TCAs, duloxetine, and carbamazepine remained unsubsidied ie not covered by PBS for use for neuropathic pain. While some drugs are actually cheap less than AUD 7 for a pack of amitriptyline 50mg X 50, the perception (and the lack of subsidiy safety net coverage) of the cost/efficacy/side-effect profile of basic drugs like amitriptyline means that there is less apparent economic and time incentive for prescribers to trial first line drugs before prescribing pregabalin. A different problem in which recommendation of these drugs for use in neuropathic pain being unlicenced/off label appears to exist in UK (ref 1 Box 2).

Furthermore Lyrica has been heavily promoted by Pifzer in Australia since its approval for PBS subsidies; the effect of which that I have seen surprising number of patients with back pain without radiculopathy on Lyrica initiated by GPs, as well as postoperative orthopaedic patients with no apparent neuropathic pain, placed on Lyrica by Acute Pain Services in various tertiary hospitals in Australia. I suspect this is to some extent the effect of big pharma advertising and prescriber (mis-) understanding of the definition of neuropathic pain.

The number of patients being started on Lyrica is at least 39% more than expected in the first year of approval by the PBAC in Australia, though it is unclear if it represent a consistent trend (ref 2)

There is no good evidence I am aware of showing pregabalin is any more effective than gabapentin or amitriptyline. I am happy to be corrected in this.

Perhaps its time to go back to look at the good old cheap and dirty rather than the new bright and shiny?

References:

1. Kalso E, Aldington DJ. Drugs for neuropathic pain. BMJ 2013;347:f7339 doi: 10.1136/bmj.f7339

2. Drug utilisation sub-committee (DUSC), PBAC, Department of Health, Australian Government. Pregabalin: 12 month predicted versus actual analysis. October 2014. http://www.pbs.gov.au/industry/listing/participants/public-release-docs/...