Pregabalins impact on opioid consumption. A comparison with gabapentin using the Norwegian Prescription Database.

By Naresh Sugandiran Kull: H10

Veileder: Jørgen Gustav Bramness Biveileder: Svetlana Skurtveit

Faculty of medicine

UNIVERSITY OF OSLO

01/10/2015

ABSTRACT

Introduction

Pregabalin's analgesic effect is disputed and the drug might have an abuse or addiction potential. We wanted to study what impact an initiation of pregabalin had on opioid consumption. We used gabapentin, another ligand for the α2δ subunit of presynaptic voltage- gated Ca2+ channels, as the comparator drug.

Materials and Methods

We extracted our data from the Norwegian Prescription Database (NorPD). NorPD covers the entire nation of Norway and all pharmacies in the country are obliged to submit data on dispensed prescriptions to the health authorities. We studied prescriptions for all patients who had been dispensed at least one prescription of either pregabalin or gabapentin in 2010. We focused on the incident users of these drugs. To study the impact on opioid use we compared the opioid consumption, measured in DDD and number of prescription, before and after.

Results

There was an increase in mean opioid consumption by 8 DDD amongst those who belonged to lowest consumption quartile of pregabalin. While the increase in opioid consumption measured by mean DDD was 251 DDD for those who belonged to highest consumption quartile of pregabalin. The same numbers amongst gabapentin users were 12 DDD and 25 DDD

Conclusions

There was a higher increase in opioid use amongst high users of these drugs compared to low users of these drugs. The increase in opioid use was much higher among high users of pregabalin compared to high users of gabapentin. These findings suggests:

1. pregabalin might only have limited analgesic effect 2. pregabalin use in high doses might have an opioid-driving effect

1 Innhold 2 Acknowledgements ...... 4

3 Background ...... 5 3.1 Pharmacoepidemiology ...... 5 3.1.1 Abuse and pharmacoepidemiology ...... 6 3.2 History ...... 6 3.3 Neuropathic pain ...... 8 3.3.1 Treatment of neuropathic pain ...... 8 3.4 Pregabalins analgesic effect ...... 9 3.5 Pregabalin and abuse ...... 10 3.5.1 Online reports ...... 10 3.5.2 Case reports and series ...... 10 3.5.3 Other studies ...... 11 3.5.4 Experiences from Adverse Drug Reactions databases ...... 11 3.5.5 Off-label use ...... 12 3.5.6 The debate on pregabalins abuse potential ...... 13 3.6 Existing pharmacoepidemiological studies ...... 13

4 Aim of the study ...... 15

5 Materials and Methods ...... 16 5.1.1 Prescription database ...... 16 5.1.2 The drugs ...... 16 5.1.3 Study population ...... 16 5.1.4 Pharmacoepidemiological parameters ...... 17 5.1.5 Flowchart ...... 18

6 Results ...... 19

7 Discussion ...... 20 7.1 Discussion of the main findings ...... 20 7.2 Strengths and weakness ...... 22 7.3 Conclusions ...... 23

8 Abbrevations ...... 24

9 References ...... 25

2 Acknowledgements

I would like to use this opportunity to thank my supervisor Professor Dr.med Jørgen Bramness. His feedback has been essential in my work with this paper. Professor Bramness has been a source of inspiration. He has undoubtfully contributed to my increased knowledge in the field of pharmacoepidemiolgy and in addiction medicine.

I would also thank my co-supervisor Svetlana Skurtveit, for giving me valuable inputs during the statistical analysis and in interpreting them.

Last, but not least I have to thank my wife, Usha, for always encouraging me and believing in me. 3 Background

3.1 Pharmacoepidemiology What is pharmacoepidemiology and why is it important?

Brian L. Strom, an acknowledged voice in scientific community and professor emeritus in epidemiology, answer to first question is; «Pharmacoepidemiology is the study of the use of and effects of drugs in large numbers of people»(1)

To answer the second question, we have to shed some lights on the current drug approval process in the US and Europe. The current drug approval process allows to prove a drug's efficacy, but it has had its limitations. At a minimum, the approval process demands that a drug should be tested on at least 500 patients in phase-3-studies. This lower limit will only reveal adverse reactions that occur in six or more patients out of per 1000 exposed to the drug. This information is not enough and gives us one of the many answers to our question number two; Pharmacoepidemiology and post-marketing studies gives us the possibility to detect uncommon effects(1).

Pharmacoepidemiology and post-marketing studies are important because of two main reasons.

1)It can supplement the information from premarketing trials:

- Giving a higher precision, i.e., to determine the incidence of a certain adverse drug reactions. - Giving a clearer picture of how the drugs work in comparison with another drug for the same indication - It can give us information about how the drug works with population that wasn't included in premarketing trials such as patients with comorbid conditions, elderly, pregnant women and children

2) It can give us new type of information which we can't get from premarketing trials such as

- Uncommon and delayed effects - Patterns of drug utilization, i.e., prescribing patterns, etc 3.1.1 Abuse and pharmacoepidemiology Drug abuse and drug dependence are difficult to study in pre-marketing studies. There are a lot of reasons for that. Firstly pre-marketing trials are time-limited and happen in controlled settings. Secondly they usually exclude patients with comorbid conditions. A third reason is that some information will never be obtainable before a drug is marketed, such as how a drug is utilized in the community. Drug utilization study can reveal phenomenons like doctors shopping which could indicate drug seeking behavior. Therefore are pharmacoepidemiological studies important.

3.2 History

Figure 1. A timeline of important events in the «history» of pregabalin.

Pregabalin was discovered by Richard Bruce Silverman and his team in the late 80s. A license agreement was signed with Warner-Lambert and Northwestern University, where Silverman worked in 1990. Phase II/III trials started in 1999 and lasted for four years. During phase II/III trials, Pfizer obtained the rights to develop pregabalin from Warner Lambert. In 2003, Pfizer filed «the new drug application» with Food and Drug Administration(FDA). In 2004, pregabalin was approved by FDA and EU(2). In both US and Europe, it was approved for treating epilepsy. It was also approved for treating peripheral and central neuropathies in Europe while only for diabetic neuropathic pain(DNP) and PostHerpetic Neuralgia(PHN) in The US. Pregabalin area of use was extended by EU in 2006 for General Anxiety Disorder while FDA approved its use for fibromyalgia in The US in 2007. In 2005, the number of users in Norway was approximately 10 000. In 2011, there were 17 000 users of pregabalin. Pregabalin reached an «all-time high» in 2007, with more than 20 000 users(3).

In 2009, Pfizer paid 2,3 billion USD to the US Government in what was the largest health care fraud case at that time of history. Pfizer was investigated due to instigations made by six whistleblowers. One of the reason behind the lawsuits was that Pfizer during the period 2005 to 2008 promoted pregabalin (Lyrica ©) for variety of off-label indications. In addition the settlement resolved allegations that Pfizer paid kickbacks to doctors to get them prescribing drugs for off-label indications. The lawsuit and settlement included in addition to Lyrica© drugs like, Bextra©, Geodon© and Zyvox©.

3.3 Neuropathic pain Neuropathic pain is defined by the International Association for the Study of Pain(IASP) as «pain caused by a lesion or disease of the somatosensory system». This definition of neuropathic pain refers to various clinical pain conditions that are often categorized by anatomical localization and etiology. Anatomically it is divided in Central Neuropathic Pain(CNP) and Peripheral Neuropathic Pain(PNP). In each of these anatomical locations various type of pathologies could result in different neuropathic pain conditions.

There are diverse terminologies associated with neuropathic pain. The abundance of terminology results from the various etiologies for neuropathies and different definitions.

There are «better» numbers for pain associated with specific neuropathic conditions than for neuropathic pain in general. A British population survey from 2006 concluded with 8 % prevalence of neuropathic pain in Britain(4). In a French postal survey with approximately 24 000 participants, 6.9 % of responders had characteristics of neuropathic pain(5). An American study by Yawn et al. using IASPs gold standard yielded a prevalence of 9.8 % for neuropathic pain(6). A Canadian telephone-based study reported an 18 % prevalence of neuropathic pain. A Brazilian cross interview survey with physical examination reported 10 % prevalence of Neuropathic pain(7)

It must be underlined that pain associated with specific neuropathic conditions gives lower prevalence than those based on IASPs definition of neuropathic pain. Van Hecke et.al concludes in their paper, based on a systematic review, including but not limited to the above- mentioned studies, that prevalence of pain with neuropathic characteristics is likely to lie between 6,9% and 10%(8).

3.3.1 Treatment of neuropathic pain A guideline issued by Norwegian Medical Association(NMA) in 2009 on pain management, recommended amitriptyline, gabapentin and pregabalin as first line treatment. NMAs guidelines also suggested Transcutaneous electrical nerve stimulation(TENS) and physiotherapy as non-pharmaceutical treatment options. NMAs guideline was based on earlier guidelines from societies like European Federation of Neurological Societies’(EFNS).

However, EFNS latest guidelines from 2010 gave different recommendations based on etiology of the neuropathic pain rather than giving a general recommendation in common(9). EFNS recommends pregabalin and gabapentin as first-line treatments for DPN, PHN and CNP. In contrary to EFNS, National Institute for Health and Care Excellence(NICE) gives a general recommendation for all type of neuropathic pain(10). NICE recommends that amitriptyline, duloxetine, gabapentin or pregabalin should be offered as the initial treatment for all type of neuropathic pain except for pain caused in trigeminal neuralgia. Capsaicin and tramadol were suggested as second-line treatment options , while strong opioids were proposed as third-line treatment(10, 11).

3.4 Pregabalins analgesic effect Pregabalin is a structural analog of GABA. Despite the similarities, pregabalin does not act as a ligand for the GABAA receptor-complex. The drug is a ligand for the α2δ subunit of presynaptic voltage-gated Ca2+ channels. This inhibits the influx of Ca2+ ions into the presynaptic membrane and prevents the release of excitatory neurotransmitters such as glutamate, noradrenaline and substance P and thereby causes a decrease in central neuronal excitability (12).

The evidence for efficacy of pregabalin in reducing pain in patients with Diabetic Neuropathic pain and postherpetic neuralgia is far better(13) than in other subgroups of neuropathic pain (14). A prospective multicenter RCT in advanced cancer patient on morphine regimen did not find any advantageous analgesic effects of pregabalin (15). Another study that looked at pregabalin's influence on opioids before and after in patients with Diabetic Peripheral Neuropathy(DPN) showed that pregabalin did not replace opioids in pain management of these patients(16). In a study from 2015 there was no statistically significant difference between pregabalin and placebo in reducing DPN pain in patients using a concomitant nonsteroidal anti-inflammatory drug (NSAID)(17). Bennet and colleagues could not draw a definite conclusion on whether pregabalin was effective or not in neuropathy in cancer patients(18). A study published by Simpsons et al. in the journal Pain did not find pregabalin to be better than placebo in HIV-associated neuropathy(19). In a Study done in 2011 in patients with central post-stroke pain, there was not significantly difference in pain reduction(20).

In a systematical review, the authors made many critical remarks on the evidence. One of the comments where that RCTs, which studied the efficacy had a relatively short duration. Another important remark made was that there might be 10 % overestimation of the efficacy of pregabalin due to publication bias(11).

Despite limited findings and sparse research in the other subgroups of neuropathy, several «societies» upheld pregabalin as the first choice for neuropathic pain in general(9, 11). These «wide» recommendations on a heterogeneous condition like neuropathy, has led scientists to raise their critical voices(21).

3.5 Pregabalin and abuse There are growing concerns among health professionals regarding pregabalin's abuse potential (22-27). The drug was put on the schedule V list in America in 2005(28) and under special surveillance in Norway in January 2010(29).

There have been some attempts to explore the abuse potential of pregabalin. According to animal studies pregabalin did not have any effect on the reward center in the brain(30). Euphoria was experienced by 4 % of pregabalin users in a large clinical controlled trial(16), whereas only 1 % of the control group experienced the same. This finding led the researchers to conclude that the euphoria could be an adverse effect of pregabalin.

3.5.1 Online reports Between June 2008 and August 2010 a group of researchers, funded by European Comission, crawled online communities for user experience. There was carried out searches that included 203 websites, whereas 108 where thoroughly monitored on a daily, weekly or monthly basis. Their study revealed some interesting user experiences(31).

One of the users of one online community wrote, "yes, it is similar to a benzo high..." about his pregabalin (ab)use(31).

Another user shared following experience at a Russian online community "when the effects wore off; I decided to shoot one capsule. That was fantastic; I felt so good!! Now I will only use the Lyrica IV."(31)

Jiang and Zheng did a data mining study on social media platform Twitter to identify effects of pregabalin. They used an algorithm to study matched effects(known effects of Pregabalin excluding euphoria). They found that 17 % of the tweet in their data mining study were about unmatched effects(32). What kind of message these tweets contained were not further described.

3.5.2 Case reports and series In 2010, the first case report on pregabalin abuse was published(33). According to the case report published in the American Journal of Psychiatry, a 47-year-old man was admitted to the Department of addiction medicine. At the time of admission the patient had consumed 25 capsules of pregabalin. A blood analysis done immediately after the admission showed a blood concentration of 29mg/l of pregabalin. This is much higher than the therapeutic concentration. The patient which were described in the case report had also admitted that he had used pregabalin with alcohol and cannabis(33).

Another interesting case report from Turkey, where you can obtain pregabalin without prescription, described yet another male who had abused pregabalin. He was put on 300mg of pregabalin for anxiety, but consumed 3000mg, multiple times intentionally to achieve euphoria(34).

A Fresh case report from India reported about a 30-year-old male who had been dependent on pregabalin for four years(35). The patient started on 75 mg of pregabalin for neuropathic pain. However, he increased it to 1500mg due to euphoria, it all ended with the patient consuming 3000mg due to tolerance, before his mother brought her son to health professionals seeking help.

In an earlier study, we found five patients who fulfilled DSM-IV criteria for dependency(25). All these patients had psychiatric co-morbid conditions. Four of five subjects that were described, in our case series, also had concomitant use of other psychotropic drugs. The highest daily dose consumed by one of the subjects were 1500/mg day. The conclusion from our earlier study was that. Pregabalin can cause dependency even if its not abused(25).

3.5.3 Other studies Grosshans et.al found in a study that about 12 % of the urine specimen taken from a patient who underwent opiate replacement therapy were positive for pregabalin even though there was no medical indication for pregabalin use(36).

A Finnish post-mortem study identified 316 cases that were pregabalin positive. 152 of the cases were suggestive of pregabalin abuse. Pregabalin was the main finding in 32 of the post mortem cases while gabapentin was the main finding in only two of the cases(37).

Another group of researchers from Finland did an analysis of serum from drivers apprehended for driving under influences of drugs in 2012(38). They detected pregabalin in 206 of 3863 samples. According to the authors, the serum level was above the therapeutical range in about 50 % of the case(38).

3.5.4 Experiences from Adverse Drug Reactions databases In Sweden like elsewhere in the world, the use of pregabalin has increased. The consumption of pregabalin for Sweden was 4,6 million DDD in 2007, and the consumption doubled to 9.3 million DDD in 2009(24). A study conducted by Schwan et.al on the Swedish Adverse Drug Reaction Reporting System, identified 198 reports indicative of abuse of 82 714 reports. Of these, there were 16 reports concerning pregabalin, reported by 14 different reporters. One of the cases reported was a female 28 years-old who took pregabalin to became high. She had mixed pregabalin with three bottles of beer. Another patient described "a feeling of being high". Another user was a 38-year-old female who said that she had a sense of being high on a dose of 600mg pregabalin. Yet another user reported that he had dissolved pregabalin in water and injected it. These are only a few of a total number of 16 reports regarding pregabalin adverse reactions reported by health personnel. Schwan et al concluded their study stating that «pregabalin is likely to have an abuse liability.»(24)

A group of German researchers found 55 reports indicative of pregabalin abuse or dependence in a German drug surveillance database(39). The researchers behind this study found that in 42% of the cases there was polydrug abuse. They also found that there were comorbid psychiatric conditions in 1/3rd of the cases(39).

3.5.5 Off-label use A study conducted in Canada by Giladi et al.explored the extend of the off-label use of pregabalin amongst patients with chronic non-cancer pain(40). They found that 71%, who met study selection criteria, used pregabalin for off-label conditions. The researchers were sure that pregabalin was mainly used off-label, particularly for low back pain.

A survey- study carried out in Lothian Region of Scotland, with a population of 750 000, covering 6 six drug abuse clinics, also had interesting findings which back up what seems like an established theory amongst doctors who work in the field of addiction. All patients who had been in the clinic for more than three months were asked to participate, and in the study period of 3month there was returned 129 questionnaires(41). Baird and colleagues discovered that 29 patient used gabapentinoids(pregabalin or gabapentin) off-label. One of the striking observation from this study was that all of them were on methadone-regimen due to opioid dependency. 76% of these 29 patients also stated that they took gabapentionoids in order to become high. 38% stated that they took gabapentionoids to potentiate effects of the methadone(41). 3.5.6 The debate on pregabalins abuse potential There has been a discussion about pregabalins possible abuse liability started in Norway in 2009. Chalabaianloo and Schjøtt had an update about on pregabalin in the Journal of Norwegian Medical Association(22). They warned about the off-label use of the medication in that article.

In 2013, a general practitioner based in Scotland, Des Spence, questioned in BMJ whether the UK was ignoring the abuse of pregabalin and gabapentin(42). He too, like many of the above mentioned authors, underlined the increased use of these substances. Marcus Bicknell,Chair of RCGPs Secure Environments group wrote in 2013 that pregabalin was "frequently requested by patients with substance-misuse problems, particularly those with opioid addiction"(43). He also underlined in the same letter to British Journal of General Practice that prison doctors were aware of pregabalin abuse potential in such settings(43).

To sum up there are reports that support that pregabalin is a potentially addictive drug, such as;

- Increased use of pregabalin - Increased off-label use - Unexpected findings of pregabalin in Opiate-addicted patients - Numerous Case-reports - Several Adverse Drug Reaction reports - Several user reports form online communities

In other hand, some critics have underlined that increased use itself does not necessary mean that drug is abused. While some other argues that one of the reasons for pregabalin being popular in addiction-circles must be that pregabalin is good for coping anxieties amongst addicted patients(44).

Hickey a pharmacist from UK pointed, in a quick responses to Des spences letter, mentioned earlier, that there is no real alternative with lesser risk and better efficacy than pregabalin in conditions like GAD and peripheral neuropathy (42).

3.6 Existing pharmacoepidemiological studies There have been conducted a few pharmacoepidemiological studies of gabapentinoids (pregabalin or gabapentin) impact on opioid use. We identified four studies which looked at gabapentinoids impact on opioid use(16, 45-47). None of those studies did a direct comparison on starters, stoppers, continuers of opioids in patients who started with either pregabalin or gabapentin.

However, one of the studies looked at gabapentins impact on opioid use in 45 patients with PHN. This study concluded that initiation of gabapentin reduced use of opioids(45). However they based their conclusion on reduction in number of opioid prescriptions.

The second study with a population size of 8004 looked at trends in opioid use before and after initiation of pregabalin(16). This study gave no information about whether there was an increase or reduction in opioid use, but gave numbers of starters, stoppers and continuers of opioids after initiation of pregabalin.

In 2007, Gore et.al published results from their study in PHN patients. They studied the change in opioid use in patients, which started on pregabalin or gabapentin. They found firstly that use of opioids increased amongst those who started on gabapentin. Secondly they found that opioid consumption (measured in the number of opioid prescriptions) was decreased amongst those who started on pregabalin(46). According to the authors, the reduction in opioid consumption was driven by «significant decrease in number of patients who received prescription for opioids in the pretreatment and follow-up period».

Gore et.al published a new study in 2011, which supported their findings from 2007(47). Their conclusion was yet again mainly based on the number of opioid prescriptions rather than dose of opioid consumption.

A striking commonality between the four studies we identified were that all of them were either funded by pharmaceutical companies or written by authors or coauthors with ties to pharmaceutical companies. Another striking commonality were that they all studied the impact on specific patient populations i.e PHN or DPN.

4 Aim of the study

Pregabalin's analgesic effect is disputed and the drug might have an abuse or addiction potential. A study done by Bramness and colleagues showed that patients starting on pregabalin managed to stop or reduce their use of benzodiazepines (48). We wanted to study what impact an initiation of pregabalin had on opioid consumption. We used gabapentin, another ligand for the α2δ subunit of presynaptic voltage-gated Ca2+ channels, as the comparator drug.

5 Materials and Methods

5.1.1 Prescription database We extracted our data from the Norwegian Prescription Database (NorPD). NorPD covers the entire nation of Norway (4.8 million inhabitants) and all pharmacies in the country are obliged to submit data on dispensed prescriptions to the health authorities. The database contains information on all prescription drugs dispensed at Norwegian pharmacies to patients. This study extracted data from 1.January 2008 to 31st December 2011. The parameters collected were: patients’ unique identifiers (encrypted), gender, age, prescribers’ unique identifiers, date of dispensing, drug name and defined daily dose (DDD). The indication for prescribing was not recorded

5.1.2 The drugs The definition of Defined Daily Dose(DDD) is «the assumed average maintenance dose per day for a drug used for its main indication in adult». DDD for gabapentin is set internationally at 1800mg per day and for pregabalin at 300mg per day by WHO. Gabapentin is covered by the Norwegian reimbursement system for epilepsy, palliative treatment and for treating chronic pain. Pregabalin is covered by the reimbursement system only for epilepsy and palliative treatment despite being registered for multiple indications. The DDD for each opioid was retrieved from WHO collaborating center for drug statistics methodology (49).

5.1.3 Study population We studied prescriptions for all patients who had been dispensed at least one prescription of either pregabalin or gabapentin in 2010. We focused on the incident users of these drugs. Incident users were defined as an individual who received the first prescription for either pregabalin or gabapentin in 2010 but had not used pregabalin or gabapentin during the two- year period before the time of prescription in 2010. Then we grouped the incident users to following four groups based on which medication they received pregabalin or gabapentin and if they had concomitant use of the other drug.

Group 1,pregabalin-group, consists of incident users of pregabalin who did not have concomitant use of gabapentin.

Group 2, gabapentin-group, consists of incidents users of gabapentin who did not have concomitant use of pregabalin.

Group 3 consists of incident users of pregabalin who had a concomitant use of gabapentin Group 4 consists of incident users of gabapentin who had a concomitant use of pregabalin

We then excluded group 3 and 4 and focused on those incident users whom only had pregabalin or gabapentin

5.1.4 Pharmacoepidemiological parameters To study the impact on opioid use we split the study group into four categories:

A) Those who did not get opioids neither before and after their first time prescription of pregabalin/gabapentin, these were termed non-opioid users.

B) Those who got opioids before initiation of pregabalin/gabapentin, but did not use it after, these were termed as Stoppers.

C) Those who did not get opioids before, but started after initiation of pregabalin/gabapentin, these were termed as Starters.

D) Those who got opioid both before and after initiation of gabapentin/pregabalin, these were termed as Continuers.

We compared the number of stoppers with the number of starters, between pregabalin and gabapentin group. We also looked at DDD and number of prescriptions, amongst those who continued with opioids.

We studied further pregabalin and gabapentin group. We stratified these two groups into four different consume quartiles; lower quartile, lower interquartile(IQ), upper IQ and upper quartile based on DDD consumptions of either pregabalin or gabapentin. We looked for any change in consumption pattern for these two groups and any difference and similarities between the similar quartile group for the comparator drug. 5.1.5 Flowchart

Figure 2. Flowchart on data selection process.

6 Results

In 2010, there were 4033 incident users of pregabalin while it was 10 995 incident users of gabapentin (Table 1). There were more female incidents users. This was true for both pregabalin and gabapentin, with respectively 55.5 % and 59.5 % of incident users being females. Most of incident users, of both drugs, were between 40-59 years of age. In average, an incident user of pregabalin got 4.7 prescriptions per year while an incident users of gabapentin got 3.7 prescriptions per year (Table 1).

9.3 % of incident users of pregabalin started on opioids after initiation of pregabalin(starters). 13.3 % of incident users stopped using opioids after initiation of pregabalin(stoppers). The most of the incident users had used opioid before initiation of pregabalin and continued consuming opioids even after an initiation of pregabalin(continuers). Continuers amounted to 47.5 percent for pregabalin. The respectively numbers for gabapentin were 9.5 % , 15.0 % and 46.6 % (Table 2). There was no significant statistical difference regarding sex when it comes to characteristics of starters, stoppers and continuers of opioids. This was true regardless of whether it was an incident user of pregabalin or gabapentin.

A deeper look on stratified data by consumption quartiles revealed more interesting data. 16,8% of incident users of pregabalin within lowest consumption quartile, managed to stop using opioids while, the number for those within the highest consumption quartile were 9.8 %. Amongst incident users of gabapentin, 15.8 % of those within the lowest consumption quartile were stoppers, but only 14.2 % of the users within the highest consumption quartile did stop consuming opioid after initiation of gabapentin.

A further analysis on continuers of opioids in both drug groups(pregabalin and gabapentin), showed an increase in consumption of opioids, measured by DDD. There was an increase in mean opioid consumption by 8 DDD amongst those who belonged to lowest consumption quartile of pregabalin. While the increase in opioid consumption measured by mean DDD was 251 DDD for those who belonged to highest consumption quartile of pregabalin. The same numbers amongst gabapentin users were 12 DDD and 25 DDD (Table 3).

7 Discussion

7.1 Discussion of the main findings First of all, there were fewer stoppers and more starters of opioids among the high users of pregabalin users compared to high users of gabapentin. Second of all there was a larger increase in opioid use amongst high users of pregabalin and gabapentin, compared to low users of these drugs. Moreover, the rise in opioid use, was much higher for the users of pregabalin than for gabapentin.

There are only a few pharmacoepidemiological studies that have studied gabapentinoids impact on opioid consumption, which also mean it is hard to compare our findings with the existing literature. But some isolated findings from different studies give us directly or indirectly numbers of starters, stoppers and continuers of opioids on patients who started with either pregabalin or gabapentin (16, 45-47). Results from two such studies, showed that there were fewer stoppers amongst those who started with pregabalin (7 %) than those who started with gabapentin (17 %) (16, 45). Data from these studies supports our first main finding.

Our second main finding showed that there was an increase in opioid use amongst high users of pregabalin and gabapentin compared to low users of these drugs. This is in accordance with a previous study performed by Gore et al. (47). They found that there was an increase in number of patients who received opioids amongst those patients who received many prescriptions of gabapentin compared to those who received few prescriptions of gabapentin. Gore et al. did similar observations when they looked at pregabalin users.

A Pfizer funded study, has previously indicated that pregabalin didn’t have an opioid driving effect. The authors of the same study underlined that there was an increased use of opioids after initiation of gabapentin (47). The latter finding is supported by our study which shows an increase in opioid use after initiation of gabapentin. However, in discordance with the Pfizer-funded study, we found that opioid-use were higher for those who started on pregabalin compared to those who started on gabapentin.

Our findings raise many questions. The first question is whether pregabalin have better analgesic properties than gabapentin or not?

All the three main findings of our study point toward an inferiority rather than superiority when it comes to analgesic effects compared with gabapentin. This is supported by a meta- analysis done by Finnerup et.al in 2015 (11). Their study showed that Number Needed to Treat(NNT) for treating neuropathy with gabapentin is a bit lesser than for pregabalin. The same study also showed that serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants, tramadol and strong opioids had lower NNT than gabapentinoids in relieving pain related to neuropathies. So far, the evidence in existing literature supports, our study, which shows that pregabalin compared to gabapentin is somewhat inferior when it comes to analgesic properties.

Our findings raised another important question; whether pregabalin is an effective analgesic drug in general? We would have expected to see either a great number of stoppers or a reduction in opioid consumption amongst continuers. This is not seen in our study (tables 2 and 3). Firstly our study revealed that most of the pregabalin users were continuers. Secondly we observed a rise in opioid use after an initiation of pregabalin. Our first observation is in accordance with the existing literature(16). But the latter one is not. In a study done by Kozma et al they found the opioid claims to be stable and concluded that pregabalin didn’t interfere with the opioid use amongst continuers(16). We couldn’t find any study which has shown an opioid-driving effect of pregabalin. On one hand, there are a lot of documentation which supports pregabalin’s efficacy when it comes to pain related to PHN and DPN. On the other hand many studies didn’t find any effects in other neuropathic conditions or in other pain conditions (15-18, 20). The latter view is to some degree supported by EFNS guidelines which gave a recommendation on the basis of subgroups of neuropathies rather than neuropathy in general (9). A meta-analysis and review on pregabalin, stated that there most probably were an over-estimation of pregabalins efficacy due to publication bias(11).

Earlier studies have shown that benzodiazepine is a predictor for later opioid use (50, 51). In one of the study the authors stated that “use of benzodiazepines was associated with increased prescription of opioids” (51). They also underlined that it was the case even after they controlled for confounders. In another study by Skurtveit et al. they studied a cohort of 17074 men and women (50). In that study they suggested on the basis of their findings that benzodiazepines were a predictor for later opioid use. What we see in our study resembles the findings from benzodiazepines-studies, too some degree. Previous prescription database studies have indicated that pregabalin might have a benzodiazepine-sparing effect (48). Authors of that study demonstrated that 15-29% of benzodiazepine users stopped using benzodiazepine after initiation of pregabalin.

The benzodiazepine-sparing effect found in that study could have at least two explanations:

a) That benzodiazepine was replaced with a drug (pregabalin) which was better b) That benzodiazepine was replaced with a drug (pregabalin) which was not better

Pregabalin in high doses seems to have an opioid-driving effect, which may support the latter explanation (b).

7.2 Strengths and weakness One weakness of this study is the study design itself, this is an observational study, and therefore there is a non-negligible possibility for confounders, such as confounding by indication.

Another weakness is that we measured opioid consumptions in DDD rather than in OMEQ. We could have a clearer picture if we converted the consumptions data to OMEQ and had stratified opioid data based on whether it was short acting , long acting, weak or strong opioids.

A third major weakness of this study was that we didn’t have diagnoses of the subjects we studied. Thus, we couldn't tell much about why pregabalin or gabapentin were prescribed. This was also one reason for that we couldn’t do a study specifically on “pain patients”. Because of non-available data on diagnosis we couldn’t neither tell anything about nor control for co-morbid conditions. There are studies which have indicated a high number of off-label use(40, 41). There is a possibility that some of our data were influenced by this phenomenon. We couldn’t tell anything about this , simply because of that diagnoses are not recorded in NorPD.

One of the biggest strength of our study is the sample size. Our study included data from approximately 15 000 users.

Another important advantage of our study is the observation time. Our study had data for one year before and after initiation of gabapentinoids. Some of the earlier pharmacoepidemiological studies had a pre-index observation of opioid data for only six months(16, 46). The relatively short time of observation in RCTs which tried studied efficacy of pregabalin, were critically remarked in a systematic review (11).

A third advantage of our study was that we had opioid consumptions measured in DDDs, while other studies had mainly published data on number of opioid prescriptions(45-47). 7.3 Conclusions To our knowledge, this is the first non-pharma funded study to analyze pregabalin and gabapentin’s impact on opioid use on population level.

There were fewer stoppers and more starters of opioids among the high users of pregabalin compared to high users of gabapentin.

There was also a higher increase in opioid use amongst high users of these drugs compared to low users of these drugs.

The increase in opioid use was much higher among high users of pregabalin compared to high users of gabapentin.

These findings suggests:

3. pregabalin might only have limited analgesic effect 4. pregabalin use in high doses might have an opioid-driving effect

However our suggestions are based on observations on a population level, thus firm conclusions cannot be made about pregabalin’s analgesic properties.

8 Abbreviations

DDD = Defined Daily Doses

CNP = Central Neuropathic Pain

PNP = Peripheral Neuropathic Pain

DPN = Diabetic Peripheral Neuropathy

DNP = Diabetic Neuropathic Pain

PHN = Post Herpetic Neuralgia

OMEQ = Oral Morphine EQuivalents 9 References

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Table 1 Incident users categorized in different groups and distribution within categories like sex and age group. (Data from Norwegian prescription database 2010). Pregabalin-users Gabapentin users

N(%) N(%) Sex Male 1794(44,5) 4457(40,5) Female 2239(55,5) 6538(59,5) Total 4033(100) 10995(100)

Age group 0-19 25(0,6) 109(1,0) 20-39 764(18,9) 1641(14,9) 40-59 1495(37,1) 4388(39,9) 60-79 1350(33,5) 3753(34,1) 80+ 399(9,9) 1104(10,0) Total 4033(100) 10995(100)

DDD Mean 109(289) 89(149) Median(Range) 25(1-7947) 27,8(0-4867) IQ Range 4,7-96,9 16,7-100

Number of prescriptions Mean 4,7(7,3) 3,7(4,6) Median(Range) 2,0(1-139) 2,0(1-58) IQ Range 1-5 1-5

Table 2 Starters, Stoppers and Continuers amongst each drug groups and consumptions quartile within these groups 1 (Data from Norwegian prescription database 2008-2011)

Pregabalin users (Group1) Gabapentin users(Group2) Pregabalin/Gabapentin Non Opioid Starters of Stoppers of Continuersof Non Opioid Starters of Stoppers of Continuers Total Total Consumption quartiles users opioids opioids opioids users opioids opioids of opioids 346(33,9) 109(10,7) 171(16,8) 394(38,6) 1020(100) 1551(31,6) 537(11,0) 776(15,8) 2039(41,6) 4903(100) Lower quartile

357(29,4) 117(9,6) 175(14,4) 565(46,5) 1214(100) 171(27,9) 56(9,1) 105(17,1) 281(45,8) 613(100) Lower interquartile

219(27,7) 63(8,0) 90(11,4) 419(53,0) 791(100) 814(28,8) 276(9,8) 391(13,8) 1343(47,6) 2824(100) Upper interquartile

283(28,1) 88(8,7) 99(9,8) 538(53,4) 1008(100) 638(24,0) 180(6,8) 376(14,2) 1461(55,0) 2655(100) Upper quartile

Total 1205(29,9) 377(9,3) 535(13,3) 1916(47,5) 4033(100) 3174(28,9) 1049(9,5) 1648(15) 5124(46,6) 10995(100)

1Data are given in numbers of individuals and percentage within the quartile group in paranteceses

Table 3 Some data on opiod use amongst those who continued with opioids after initiation of pregabalin, grouped after DDD use of pregabalin and gabapentin. (Data from Norwegian prescription database 2008-2011) Pregabalin users (Group1) Gabapentin users (Group2) Number of Number of Opioid Number of Number of Opioid Pregabalin/Gabapentin opioid opioid use Opioid use opioid opioid use Opioid Consumption prescriptions prescriptions before after Change prescriptions prescriptions before use after Change quartiles before after (DDD) (DDD) in DDD before after (DDD) (DDD) in DDD Lower Quartile DDD

Mean 7(10) 7-(10) 113(219) 121(198) 8 8(14) 8(13) 144(236) 156(259) 12 (STD)

Lower IQ DDD Mean 8(11) 7(10) 150(246) 143(244) -8 8(11) 8/10) 157(317) 158(283) 1 (STD)

Upper IQ DDD Mean 10(10) 9(11) 196(298) 229(356) 9(11) 9(11) 178(345) 194(357) (STD) 33 16

Upper Quartile DDD Mean 12(13) 16(17) 290(575) 541(1533 ) 11(13) 12(15) 214(328) 239(320) (STD) 251 25