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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 35  |  Issue : 1  |  Page : 46-51

A prospective observational study to assess drug aberrant behaviours in chronic pain patients on gabapentinoids


1 Chronic Pain Service, Sheffield Teaching Hospitals NHS Trust, Sheffield, UK
2 Department of Anaesthesia and Pain Management, St John's National Academy of Health Sciences, Bengaluru, Karnataka, India
3 Department of Biostatistics, St John's National Academy of Health Sciences, Bengaluru, Karnataka, India

Date of Submission11-May-2020
Date of Decision18-Jun-2020
Date of Acceptance14-Aug-2020
Date of Web Publication27-Apr-2021

Correspondence Address:
Dr. Sangeeta Das
6052, Sobha Daffodil Apartments, HSR Sector 2, 27th Main, Bengaluru - 560 102, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpn.ijpn_64_20

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  Abstract 

Aim: The aim is to explore whether addiction or drug aberrant behavior exists among patients being treated with pregabalin or gabapentin in our outpatient service. Methods: A self-administered questionnaire, the current opioid misuse measure (COMM) was distributed to all patients attending the outpatient service. They filled this voluntarily with maintenance of complete anonymity and confidentiality. Statistical analysis was conducted using the SPSS software. Results: A total of 52 questionnaires were received. Twenty-one patients were on gabapentin and 19 on pregabalin. Eighty percent of the patients had little or no benefit and yet an attempt to taper the doses was made only in 37.8% patients. About 56.9% patients had COMM scores above 9, the cut off value for detecting drug abuse/misuse. The COMM scores showed a positive association with the dose magnitude of gabapentin (P = 0.006) but not pregabalin. They also showed a significant positive correlation with the duration of treatment with pregabalin (P = 0.000). The Mann–Whitney U-test showed that the COMM scores were significantly higher in the pregabalin group (P = 0.022). Conclusions: Our findings suggest gabapentinoids do carry a potential risk of addiction. Pregabalin more than gabapentin may have a potential for drug aberrant behavior. We must regularly review patient's doses and duration of treatment. Large scale studies are needed to validate the findings. Setting up of national pharmacovigilance databases may be the way forward in preventing a potential drug abuse problem.

Keywords: Gabapentanoids neuropathic addiction


How to cite this article:
Berwertz M, Das S, Raj JM. A prospective observational study to assess drug aberrant behaviours in chronic pain patients on gabapentinoids. Indian J Pain 2021;35:46-51

How to cite this URL:
Berwertz M, Das S, Raj JM. A prospective observational study to assess drug aberrant behaviours in chronic pain patients on gabapentinoids. Indian J Pain [serial online] 2021 [cited 2021 Sep 24];35:46-51. Available from: https://www.indianjpain.org/text.asp?2021/35/1/46/314702


  Introduction Top

The Neuropathic Special Interest Group (NeupSIG) of the International Association for Suicide Prevention (IASP) has redefined neuropathic pain as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” This is a shift from the old definition that defined neuropathic pain as “pain caused by a lesion or dysfunction of the nervous system.” The word dysfunction which meant long standing nociceptive pain with neuroplastic changes is now replaced by disease.[1] The prevalence of neuropathic pain is estimated at about 3.3%–8.2% of the general population.[2]

The international classification of diseases (ICD) 11 has now given us some clarity on the existence of chronic neuropathic pain as a separate entity by itself, further classifying into peripheral and central neuropathic pains by the interdisciplinary task force of IASP.[3] In 2016, Kosek et al. proposed the term “nociplastic pain” to describe/define certain conditions that were neither classical nociceptive pain nor neuropathic. The term was accepted by the IASP council in 2017 and “Nociplastic pain” was defined as “Pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.”[4],[5]

Neuropathic medications have been largely used to treat neuropathic pain and now what we know as nociplastic pain. An example of nociplastic pain could be some fibromyalgias or chronic nociceptive arthritic pains with neuropathic features. There are different neuropathic treatment guidelines available from NeuPSIG IASP group, the European Federation of Neurologists, and the Canadian Pain society.[2],[6]

Gabapentinoids are used as first line medications in all the guidelines. Gabapentin and pregabalin act on the presynaptic voltage gated calcium channels in the dorsal horn and therefore reduce the release of presynaptic excitatory neurotransmitters. Both gabapentin and pregabalin have been extensively studied in pure neuropathic pain conditions mainly diabetic neuropathy and post herpetic neuralgia. The efficacy of a drug can be quantified using the numbers needed to treat (NNT). The NNT is the number of patients that need to be treated with a particular drug for one patient to have at least 50% pain reduction. NNT of pregabalin is reported as 7.7 versus 7.2 for gabapentin.[7]

However, like all drugs the gabapentinoids also have side effects such as dry mouth, blurred vision, sedation, dizziness, weight gain, constipation, and leg swelling. The patient education regarding these side effects is crucial in ensuring their compliance. There has been recent speculation on potential addiction problems and drug abuse/misuse of these drugs. The Public Health of England produced some guidance regarding the safe prescription of these drugs accepting the potential for dependence, addiction, and misuse.[8] There were many drug deaths reported in the western countries in the following years thus mandating the governments to reclassify pregabalin and gabapentin a Class C controlled drug in the UK and the US.[9]

Aim

Our aim was to explore whether the potential addiction with gabapentinoid drugs could be a problem in our pain service? Opioid addiction is a well-known phenomenon, well studied with many validated tools such as the current opioid misuse measure (COMM) and the Screener and Opioid Assessment for Patients with Pain; that can be used to identify abuse/misuse. There are no such validated tools for gabapentin or pregabalin. We hypothesized that since the outcome of the questionnaires is solely dependent on behavioral patterns, therefore the same questionnaires could be used to identify potential addictive behavior in different drugs. We therefore decided to use the COMM questionnaire to identify concurrent misuse/abuse of pregabalin and gabapentin within our outpatient service.


  Methods Top

After receiving approval from the local ethics committee, the COMM questionnaire was given to those patients visiting the outpatient pain service, who were identified by the consultant to be on gabapentin or pregabalin. It was a self-administered questionnaire filled up on a voluntary basis. The questionnaire was limited to English speaking patients only. The patients were given typed patient information sheet before filling the questionnaire to explain the questionnaire is voluntary and anonymous as well as kept strictly confidential. No information that could identify patients such as name or hospital number was collected to ensure anonymity. The patients dropped their filled questionnaires in a collection box.

Categorical data were analyzed as absolute numbers and percentages whereas quantitative data was expressed as median with interquartile range (IQR), since the data did not exhibit normal distribution. The Pearson's Correlation coefficient was used to test the relationship between the COMM scores and doses or duration of drug therapy. The Mann–Whitney U-test was used to compare the COMM scores between the two gabapentinoids. Statistical significance of P value is considered at 5% level of significance.


  Results Top

We received 52 questionnaires over a 1 month period. However, 12 patients were excluded as they were also receiving opioid therapy. There were 21 patients who were on gabapentin and 19 patients on pregabalin.

The drugs were commenced by general/family physicians in 61.5% cases and pain physicians in 27.5% cases. 10% of cases had the drugs prescribed by other specialists such as neurosurgeons, neurologists or orthopedic doctors.

The gabapentinoids were largely prescribed for neuropathic pain conditions. They were most frequently prescribed for back pain with radiculopathy (45.9% of all cases). Other conditions included postsurgical pain, complex regional pain syndrome, peripheral neuropathy, and nerve entrapments (27%). They were also prescribed for nonneuropathic conditions as mentioned in [Table 1].

Table 1: Specialty commencing drugs and their indications

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Most patients had been established on the therapy for an average of 36 months (range 2–144 months). The minimum period was 2 months. We understand that the recommended trial period for neuropathic agents is at least 6–8 weeks. The dose ranges of the drugs were extremely variable with median dose of gabapentin being 1800 mg and median dose of pregabalin 300 mg. Details are mentioned in [Table 2].

Table 2: Dose ranges of the drugs as well as use of concomitant medications

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About 51.3% of the patients were on other neuropathic pain medications as well. Among these tricyclic antidepressants (TCA) were the most commonly used concomitant medication (29.7%). This was followed by a either a selective serotonin reuptake inhibitor or a serotonin noradrenaline reuptake inhibitor (SNRI) combination in 18.9% patients.

A descriptive Likert like scale was used to assess effectiveness of the drugs. Only 5% of the patients said their pain was very much reduced. 15% of the patients claimed their pain was much reduced. However, 80% patients had either no reduction in pain at all (25%); only slight reduction (45%) or were unsure (10%). We could not use numerical rating scale (NRS) or visual analog scale (VAS) scale as objective measures, as most of the medications were commenced by the general/family physicians and therefore no baseline scores were available.

Dry mouth, drowsiness, and mood changes were by far the most common side effects occurring in 45%, 32.5%, and 50% of the patients, respectively. These were followed by constipation and weight gain found in 35% and 25% of the cases. Less common side effects were dizziness, blurred vision, leg swelling, and memory loss. Gabapentin and pregabalin had almost similar side effect profiles. However, dry mouth, weight gain, drowsiness, and blurred vision seemed to occur more frequently in the pregabalin group [Table 3].

Table 3: Side effects of gabapentin and pregabalin

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We looked at whether there was an attempt to reduce these drugs when indicated. We found that 23 out of the total 37 patients (62.1%) never even attempted a dose reduction. Among them 60.8% patients were not aware that this could be an option. The remaining 9 (39.2%) patients did not want to try fearing an aggravation of symptoms or having only recently been commenced on the therapy.

An attempt at reduction of the dose was made by 14 out of 37 patients (37.8%) out of which only four patients did it successfully, whereas 10 were unsuccessful as symptoms returned [Table 4].

Table 4: Trial reduction of gabapentanoids

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The main aim of the study was to see if the COMM scores indicated whether the gabapentinoid group of drugs can potentially lead to drug abuse behaviors. A COMM cut off score of 9 points and above indicated a possibility of drug aberrant behavior.

About 56.7% patients scored above the cut off of 9. The vast majority of these patients scored between 10 and 19 (29.7%) and between 20 and 29 (16.2%). Only four patients in total scored above 30 [Table 5].

Table 5: Distribution of number of patients in each Current Opioid Misuse Measure score category

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We also tried to explore the correlation between the COMM scores, duration of treatment, and dose magnitudes. We did not find any association between the COMM scores and duration of treatment (Spearmans rho 0.129 with P = 0.438). We looked at the association between the COMM scores and doses independently in the gabapentin and the pregabalin group. The doses in the gabapentin group had a positive association with the COMM scores (Spearman's Coefficient 0.577 with P = 0.006). The same sort of association was not however seen in the pregabalin group (Spearman's Coefficient −0.330 and P = 0.195). Although in the overall study cohort as said earlier COMM scores were independent of the duration of the treatment, an individual group analysis revealed this was not the case in the pregabalin group. The duration of treatment with pregabalin and the COMM scores showed a significant positive association (Spearman's 1.0; with P = 0.000).

The COMM scores in both the gabapentin and pregabalin group were compared. As the data were non parametric, comparing the median p50 values revealed the pregabalin group had a much higher p50 value of 16 (IQR p25: p75; 10–23) than the gabapentin group which had a p50 value of only 6 (IQR p25: p75;1–15).

The Mann–Whitney–U-test was used to compare the COMM scores between the two drug groups. The COMM scores were shown to be significantly higher in the pregabalin group (P = 0.022).

The percentage of patients in the pregabalin group scoring a COMM value above 9 was 73.7% compared to 38.1% in the gabapentin group, suggesting that a greater proportion of patients on pregabalin exhibited potentially drug abuse behaviors.


  Discussion Top

It was not until 2010 that the initial reports of abuse of gabapentinoid class of drugs started appearing. The pharmacovigilance databases of the UK, Scandinavia, and Germany started getting increasing reports of gabapentinoids abuse. The Eudravigilance database analysis showed 4301 records of gabapentin abuse and 7639 records of pregabalin abuse from 2004 to 2015.[10],[11]

Addiction, substance use disorder or substance misuse are all now under one common term “Dependence syndrome” defined by the ICD-10 as “A cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.”[12]

Our pain service sees about 600–800 patients in a month. Despite a busy service, the number of patients who voluntarily and anonymously filled up these questionnaires was low with a good number of them having to be excluded as they were on opioids. We felt that there might have been some hesitation in filling up the questionnaires. Nevertheless, ours is one of the few studies that have used a self-administered questionnaire. Other methods used in literature to a study potential addiction are mainly using database analysis or online surveys.

In most cases, the drug was commenced by general physicians. Pain physicians were responsible only for a third of the prescriptions. Most had been prescribed for classical neuropathic conditions and some cases fell into a borderline of possibly mixed pain or what we now call nociplastic pain such as long term arthritis and fibromyalgia.

The dose ranges varied widely. Doses for gabapentin started at 150 mg and went up to the maximum dose of 3600 mg (median dose = 1800 mg). Similarly for pregabalin doses ranged from 50 mg to higher than maximum dose of 1200 mg (median dose = 300 mg). The average duration was about 36 months with the minimum being 2 months which is the recommended minimum trial period to assess the response of the drug. Combinations therapies are fairly common to use in neuropathic pain as they rarely respond to a single agent. The most common combination was with TCA (29.7%) followed by SNRI's (18.9%) which fits in with standard practice.

We could not use an objective efficacy scale like the NRS or VAS score as we did not have baseline values at the time of commencing the drug. Therefore, we used a descriptive scale to assess the degree of pain reduction. Only 5% of the patients said the pain was very much reduced. The majority 80% patients fell into a category of either slight reduction of no reduction. However, as a clinician, we always have to consider benefit versus risks. The side effects were present in about 45% of the patients. Despite the low efficacy and the common issues with side effects there was no attempt at tapering or stopping the drug in 62.1% patients. This suggests that we need to constantly monitor these patients using the 4 As of Passik et al. Analgesia, activities of daily living, adverse events, and aberrant drug-related behavior.[13] If the risks outweigh the benefits or the drug is ineffective, we should look at being proactive in tapering the drug.

The COMM Scores showed some concern. Before we discuss results, it is necessary to understand the COMM Scoring system. COMM is a validated self-assessment questionnaire used to identify drug aberrant behaviors in patients on chronic opioid therapy.[14] The questionnaire contained a total of 17 items covering six key elements:

  • Signs and symptoms of intoxication
  • Emotional volatility
  • Evidence of poor response to medications
  • Addiction
  • Healthcare use patterns
  • Problematic medication behavior.

Each item scores between 0 and 4. A total score ≥ 9 is indicative of drug aberrant behavior.

The COMM as the name suggests identifies concurrent misuse, therefore helping clinicians to monitor drug aberrant behaviors over the course of treatment. It has been validated in approximately 500 chronic pain patients.[12] It is a very sensitive test which means that there are going to be a significant number of patients who are false positive. These patients should not be denied pain treatment on this basis. Monitoring should be put in place and further assistance through addiction specialists should be sought to confirm the suspicions.

Our concern was that more than half the patients (56.7%) scored about the cut off value of 9. That does not equate to them all showing addictive behavior. The COMM is a sensitive questionnaire and it is designed more as a potential warning indicator. This needs further investigation to confirm true drug aberrant behavior.

We looked at the relationship between COMM scores and dose magnitudes as well as the duration of treatment. We did not find any association with the COMM scores and the duration of the treatment. However, when compared to the duration of treatment of individual drugs there seemed to be a positive association with the duration of the treatment of pregabalin. With the respect to dose magnitude the results suggested a positive association with dose magnitudes of gabapentin and the COMM scores, but no association with dose magnitudes of pregabalin. Although statistically significant, since our numbers are small we would refrain from making any emphatic conclusions.

On comparison of the COMM scores between the two drugs, the median p50 value of Pregabalin was significantly higher than the p50 value of gabapentin (16 vs. 6; P = 0.022). In addition we found that a greater proportion of patients in the pregabalin group than gabapentin, scored above the cut off COMM value of 9 (73.7% vs. 38.1%).

We confirmed this conclusion by studying available literature. A population based cohort study in France concluded that misuse was more frequent in the 8692 new users of pregabalin (12.8%) than in the 1963 gabapentin (6.6%) or the 3214 duloxetine (control group) new users (9.7%) (P < 0.001)[15] The study mainly looked at misuse which they defined as using higher doses than prescribed or advised. This may have been due to two reasons, either to manage uncontrolled pain or abuse of the drug for recreational purposes. The authors were unable to differentiate between the two in their data.

A systematic review consisting of 106 studies looked at three different aspects of gabapentinoids, those that studied the rewarding behavior, those that studied the prevalence of dependence using the ICD-10 criteria and those that studied overdose deaths among this cohort of patients.[10] They concluded that although aspects around gabapentin seems to revolve around more of a rewarding behavior and withdrawal effects; pregabalin is the more likely one to be associated with the more pathological dependence syndrome. The reasons postulated were a high bioavailability (90% vs. 33%–66% gabapentin), with rapid onset of euphoric effects and linear kinetics that seem to make it more liable to dependence than gabapentin.[16]


  Conclusions Top

We therefore conclude that patients on gabapentinoids drugs do carry a potential risk of developing drug dependence behavior. The dose and duration of the drugs have a positive association with the likelihood of developing drug abherant behavior. The above findings should serve as a forewarning to a potential crisis. There are stringent practices in place for opioids but not for neuropathic drugs, which can be prescribed by any physician irrespective of grade or specialty. The findings also suggest that physicians need to justify their choice of pregabalin over gabapentin, given the increased risk of dependence with pregabalin. The patients should be regularly monitored and in case of the drug being ineffective the drug must be tapered or stopped.

Further studies on a large scale would be useful to confirm the above findings. There are limitations to conducting controlled trials in this case, however, serious consideration must be given to setting up national pharmacovigilance databases to combat any possible crisis in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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2.
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Mayor S. Pregabalin and gabapentin become controlled drugs to cut deaths from misuse. BMJ 2018;363:k4364.  Back to cited text no. 9
    
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WHO ICD-10 Classification Of Mental And Behavioural Disorders. Available from: https://www.who.int/substance_abuse/terminology/en/. [Last accessed on 2020 Apr 16].  Back to cited text no. 12
    
13.
Passik S, Kirsh K, Whitcomb L, Theobald DE. Pain clinicians' rankings of aberrant drug-taking behaviors. J Pain Palliat Care Pharmacother 2002;16:39-49.  Back to cited text no. 13
    
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Butler S, McCaffrey SA, Villapiano AJ, Jamison RN, Butler SF. Development and validation of the current opioid misuse measure. Pain 2007;130:144-56.  Back to cited text no. 14
    
15.
Driot D, Jouanjus E, Oustric S, Dupouy J, Lapeyre-Mestre M. Patterns of gabapentin and pregabalin use and misuse: Results of a population-based cohort study in France. Br J Clin Pharmacol 2019;85:1260-9.  Back to cited text no. 15
    
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Bockbader HN, Wesche D, Raymond M, Chapel S, Janiczek N, Burger P. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharma-Cokin 2010;49:661-9.   Back to cited text no. 16
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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