Gabapentinoids association with severe COPD exacerbations

 A population-based observational study found that gabapentinoids (gabapentin and pregabalin) were associated with severe COPD exacerbations (see gabapentin assoc severe COPD AnnIntMed2024 in dropbox, or  doi:10.7326/M23-0849)

 

Details:

-- a large data-mining study from Québec accessed three computerized healthcare databases, collecting information on demographics, medical services, and dispensed outpatient prescriptions. this included information on medical services for all Québec residents (though one of the databases only included those who did not have private medication insurance, 43% of the population). These researchers also accessed information on all hospitalizations, procedures, and vital statistics including date, cause, and place of death

-- there were some differences in the demographics and comorbidities of those individuals on gabapentinoids, based on whether they were used for epilepsy, neuropathic pain, or other chronic pain. But overall baseline findings:   

    -- mean age 74, 58% female

    -- hospitalizations for COPD: zero in 88%, one in 9%, at least two in 4%; moderate or severe COPD exacerbation zero in 64%, one in 20%, at least two in 16%; number of bronchodilators used (long-acting beta agonist LABA, long-acting antimuscarinic antagonist LAMA) zero in 14%, one in 49%, two in 36%; inhaled corticosteroids ICS 72%, short-acting beta agonists 65%, ipratropium 14%, prednisone 33%, methylxanthines 3%, respiratory antibiotics 62%

        -- number of hospitalizations overall: zero in 45%, 1 in 28%, at least two in 30%

    -- comorbidities: hypertension 86%, diabetes 36%, CAD 55%, stroke/TIA 18%, heart failure 26%, dyslipidemia 66%, cancer 30%, chronic kidney disease 23%, dementia 14%, liver disease 9%, anxiety 37%

    -- drug misuse in 3%, alcohol misuse in 10%

    -- number of different medication classes: 0-8 in 9%, 9-11 in 15%, 12-15 in 30%, >15 in 48% [ie, 78% were on lots of different types of meds]

        -- medications: antiplatelet 58%, oral anticoagulants 17%, beta blockers 35%, antiarrhythmics 50%, NSAIDs 38%, opioids 50%, benzos 58%, antipsychotics 16%, antidepressants 33%, PPIs 70%, oral steroids 3%, barbiturates 3%

 

-- Patients with COPD were identified by using a base cohort of all those at least 55 years old who received three or more prescriptions for a respiratory drug (LABA, LAMA, the combination of LABA-LAMA or LABA-ICS) on at least two different dates within a one-year period between 1994 (when gabapentin was approved) and 2015

    -- this cohort was restricted to patients who had at  least 12 months of drug coverage and no prescription for LABA or LAMA in the year before the first of the three qualifying prescriptions (LABA, LAMA, ICS)  [ie, the cohort were new users of these COPD meds]

    -- they excluded patients who had a diagnosis of asthma during a hospitalization; had a prescription for more specific asthma medicines (nedocromil, ketotifen, cromolyn, or anti-leukotrienes); or in those who received gabapentinoids at any time before cohort entry

-- those receiving gabapentinoids were compared to individuals who were not exposed to gabapentinoids, with matching 1:1 by TCPS (time-conditional propensity score) matching, a statistical methodology for equalizing severity of disease as well as general demographics/medications/etc between those receiving gabapentinoids versus the non-gabapentinoid comparator group

 

-- primary outcome: severe COPD exacerbation, defined as a first hospitalization with admission for or primary diagnosis of COPD during follow-up, or death due to COPD exacerbation

-- secondary outcomes: moderate or severe COPD exacerbation (with moderate COPD exacerbation being defined as a new prescription for oral prednisone) and respiratory failure (defined as a combination of respiratory failure with COPD; pneumonia, or mechanical ventilation; or death from respiratory failure or COPD as a primary cause, using a rigorous definition of respiratory failure)

-- secondary analyses: whether the risk for severe exacerbation varied with duration of gabapentinoid use; whether the risk varied with age, sex, moderate or severe COPD exacerbation, ICS use, number of classes of respiratory medications prescribed in the year before cohort entry, and benzodiazepine or opioid use at cohort entry

 

-- mean follow-up 1.6 years, and mean treatment duration was 0.5 years                                                                                                                            

 

Results:

-- 156,813 patients were identified with COPD, using the above criteria:

    -- 356 gabapentinoid treatment initiators had epilepsy; 9411 had neuropathic pain; 3737 had other chronic pains; those receiving gabapentinoids were sicker with more comorbidities and markers of overall health, and had more medication use for all indications. After TCPS matching, the groups were well-balanced except for the specific group who had epilepsy and chronic kidney disease

 

-- primary outcome: gabapentinoids were associated with increased risk of severe COPD exacerbations across all of their indications:

    -- epilepsy: 58% increased, HR 1.58 (1.08-2.30)

    -- neuropathic pain: 35% increased, HR 1.35 (1.24-1.48)

    -- other chronic pain: 49% increased, HR 1.49 (1.27-1.73)

        -- there was also no difference using a 15- or 30-day grace period, follow-up being limited to one year, or excluding patients with a history of cancer. The only difference was in the analysis by intention-to-treat exposure (i.e. all of the patients in the gabapentinoid group, including those who do not take them): they had statisticallysignificantly increased incidence of severe COPD exacerbations for only neuropathic pain, with an increased risk of only 16%

    -- all of the individual curves demonstrated increased severe COPD exacerbations within 3 to 4 months of initiating the gabapentinoids, with further divergence of the curves for about three years; here is the summary graph:

 

 

-- there was also increased risk for moderate or severe COPD exacerbations and respiratory failure in patients with neuropathic pain and other chronic pain (for those with epilepsy, these estimates were limited, likely attributable to the low number of patients in this group)

 

--subgroup analyses:

    -- no difference in any of their subgroups: for those 55-74yo versus older, female versus male, history of prior COPD exacerbation, or the use of benzos/opioids at cohort entry

    -- gabapentinoids remained associated with severe COPD risk when compared to NSAIDs

 

-- The risk of severe COPD exacerbations was similar in patients on gabapentin versus pregabalin

 

Commentary:

-- gabapentinoids are often used for several off-label indications, and in many cases the results (when actually studied) do not support their use

    -- though there are some differences depending on how the systematic review/meta-analysis was done, several meta-analyses have not found benefit from gabapentinoids for low back pain or radicular pain: https://gmodestmedblogs.blogspot.com/2018/07/gabapentinoids-still-not-help-low-back.html

    -- a recent RCT found that gabapentin was ineffective for chronic pelvic pain in women: https://gmodestmedblogs.blogspot.com/2020/10/chronic-pelvic-pain-gabapentin.html

    -- despite these negative studies, several guidelines still suggest using gabapentinoids as first-line pharmacotherapy for neuropathic pain (without mentioning potential respiratory adverse effects), though the evidence for medication benefit seems to be better for duloxetine or venlafaxine

 

-- and, we know of significant adverse effects of gabapentinoids, beyond the typical mood changes, drowsiness/dizziness, GI adverse effects, etc.:

    -- the FDA in 2020 had an official warning about gabapentinoids and respiratory depression: https://gmodestmedblogs.blogspot.com/2020/01/fda-warning-gabapentinoids-and.html . Though this was based on a relatively small number of reports, I believe we all are aware that there is major underreporting of adverse events to the FDA, either because of an unknown association (if we clinicians were not attributing gabapentinoids to respiratory depression, but simply attributing the exacerbation to the underlying lung disease,; we may therefore not process that the linkage might have been with gabapentinoids and report the adverse association), or because of simply lack of reporting (as a result of being busy clinicians with not much time to do the extra step of formal reporting)

    -- the advantage of the above Canadian study is that it is a population-based sampling, not requiring formal reporting processes

-- a complicating factor for patients with COPD is the frequency of comorbidities. Some of these may well be related to medical conditions associated with smoking/occupational exposures/environmental exposures that might have caused the COPD; also there is a large percentage of patients who have pain-related diagnoses: a retrospective study of almost 8000 patients with COPD found that 60% had chronic pain, 41% used pain-related medications (including short-acting opioids in 24% and long-acting opioids in 4%), and 71% had at least one outpatient pain or pain-related medication: see https://pubmed.ncbi.nlm.nih.gov/23952846/ )

-- there also seem to be adverse respiratory effects even in patients without clear prior respiratory issues: one small study of men without sleep apnea were randomized to gabapentin 300 mg at night versus placebo, and polysomnography found significantly higher apnea-hypopnea index in those on gabapentin: https://pubmed.ncbi.nlm.nih.gov/28116804/

-- the authors of this current study also cite articles finding that in surgical settings for different procedures, use of gabapentinoids preoperatively was associated with respiratory depression

 

-- This well-designed Canadian study did find a clear association between gabapentinoid usage and the risk of severe exacerbations of COPD in patients on gabapentinoids for several medical conditions (epilepsy, neuropathic pain, other chronic pain), and this was true independent of age, sex, and several markers of COPD severity. A very important feature of this study was not just its pretty meticulous design, but also the very large numbers of people enrolled with a general population-based sampling

-- and these results are consistent with the smaller studies and the FDA official warning

 

-- one of my real concerns from this article is that older patients (as in this study) may well have decreased kidney function (at least 90% of mine do…), and the gabapentinoids are excreted largely intact by the kidneys, requiring renal dosing. so this raises a few issues:

    -- we do not get accurate eGFRs by our standard blood tests (creatinine, cystatin; as noted in https://gmodestmedblogs.blogspot.com/2022/07/egfr-not-such-great-estimate-of-renal.html ), though cystatin is likely a better estimate in older people with less muscle mass. And cystatin, it seems, is a better predictor of adverse events than creatinine: https://gmodestmedblogs.blogspot.com/2023/12/cystatin-c-better-predictor-of-bad.html . and, per the former blog, our GFR estimates overall can vary 2 CKD stages from the actually measured GFRs (ie, we may think someone has a marginally acceptable eGFR for the meds, but in fact the measured GFR is actually much lower)

    -- many patients on gabapentinoids (especially for chronic pain or neuropathy) are often on other meds that cause respiratory depression (opiates, benzos), and these meds also may have decreased metabolism/excretion as patients age: benzos are metabolized in the liver by the CYP P450 system, and active metabolites are excreted in the urine; opiates are largely metabolized in the kidneys (morphine) with about a 20% decreased metabolism in the elderly; other opiates do have somewhat different metabolisms, though renal dose adjustment is recommended for almost all of them: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704133/ . So, the kidneys are most often involved in all of these meds… And reduced kidney function with aging may increase the risk of adverse effects (eg respiratory failure)

    -- however, unexpectedly (to me), the subgroup analysis in this study of those also taking benzos/opioids at cohort entry did not have a relationship with severe COPD exacerbations in those on gabapentinoids vs those not, suggesting that adding gabapentinoids to these drugs did not add substantively to the risk of severe COPD exacerbations. Not sure how to explain that adding a 3^rd respiratory depressant to one or two others does not make things worse for those with COPD

-- and, and, and: there is concurrent progressive decrease in lung function, beginning at the ripe old age of 20-25yo (https://pubmed.ncbi.nlm.nih.gov/18046878/ )

   -- so, the rather adverse combination of respiratory depressants along with decreasing renal metabolism of them leading to higher systemic drug  levels together with decreasing respiratory system functioning would seem to be an inopportune situation.....  and perhaps should be rigorously studied??? one easy start might be with polysomnography as in the above study

 

Limitations:

-- this study involved older and very sick patients with COPD, with multiple comorbidities, multiple different classes of medications taken, as well as multiple hospitalizations for other reasons. This might limit generalizability to those with less severe COPD or other comorbidities (although COPD is often associated with other comorbidities, given their likely relationship with smoking and the associated multisystem adverse systemic consequences)

-- also, this study would not necessarily apply to those with other lung diseases (asthma, interstitial lung disease, etc), or to those with sleep apnea, or to those without lung disease. but there is still concern about the metabolism of gabapentinoids with aging and deteriorating renal function

-- the general methodology in this large data mining study was overall quite impressive in identifying COPD, and eliminating those with the most common potential confounder of asthma. though, that being said, there certainly is a potential error by not having a formal RCT.

    -- and as an observational study, there might well be unmeasured confounders that might have influenced the COPD exacerbations, such as exposure to passive smoking, air pollution, stress, lack of exercise, etc. Therefore, the results in this study, though confirmatory of the results of the small studies noted above, can only be interpreted as an association and not as causality

 

So, yet another reason that gabapentinoids should be avoided whenever possible, with a few comments:

-- there were real drug shenanigans in the early gabapentin studies suggesting benefit: the first article I saw was in JAMA reported that high-dose gabapentin was associated with decreased peripheral neuropathy symptoms.  This study was probably published 25-30 yrs ago, but I was unable to find the reference. But another drug-company sponsored study with even more patients was never published….  

    – And the fact that several current studies and meta-analyses noted above did not find benefit of gabapentinoids reinforces their lack of real utility

-- though some guidelines still suggest gabapentinoids as first-line therapy for post-herpetic neuralgia, other meds work quite well, including tricyclic antidepressants and duloxetine

-- and, as per many of the chronic pain guidelines, we should be pursuing the many documented nonpharmacologic approaches first, combined with meds as needed: the blog https://gmodestmedblogs.blogspot.com/2023/02/pain-management-review-of.html includes assessment of antidepressants for chronic pain management, but also has reference to many other blogs on benefits of mindfulness, early PT for sciatica, cognitive behavioral therapy, stress reduction, group therapy, nonopioid meds; and there are other blogs on tai chi as in https://gmodestmedblogs.blogspot.com/2017/06/tai-chi-for-knee-oa-mindfulness-for.html

 

geoff

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