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#432 Hotcakes: E-cigarettes for smoking cessation, Gabapentin and COPD exacerbations, Lidocaine for neck pain, C diff risk by antibiotic type, and “dosing by clicks” for GLP1’s

March 25, 2024 | By

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Join us as we review recent practice-changing articles on E-cigarettes for smoking cessation, Gabapentin and COPD exacerbations, lidocaine patches for mechanical neck pain, Cdiff risk by antibiotic type, and “dosing by clicks” for GLP1 agonists. Fill your brain hole with a delicious stack of hotcakes! Featuring Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), and Matt Watto (@doctorwatto).

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Show Segments

  • Introduction and disclaimer
  • E-cigarettes for smoking cessation
  • Gabapentinoids and COPD exacerbations
  • Topical lidocaine for neck pain
  • Association between specific antibiotics and C. diff infection
  • Shortage of GLP-1 agonists and “dosing by clicks”

Hotcake #1: E-cigarettes for smoking cessation: ESTxENDs (Paul)

Auer R, et al. Electronic Nicotine-Delivery Systems for Smoking Cessation. N Engl J Med. 2024 Feb 15;390(7):601-610. doi: 10.1056/NEJMoa2308815. PMID: 38354139. 

What was the research question? Does the use of electronic cigarettes (e-cigarettes), in addition to standard of care cessation counseling, increase rates of abstinence from smoking at six months?

Why is this study important? Many patients who smoke are interested in using e-cigarettes as a cessation aid. Evidence suggests vaping is more effective than nicotine replacement therapy, but few studies have examined the long-term safety or efficacy of e-cigarettes for this purpose.

How was the study done? This was an open-label, randomized superiority trial done at 5 sites in Switzerland from 2018 – 2021. Eligible participants specified a quit date before 1:1 randomization to either the intervention group (counseling plus free e-cigarette starter kits and replacement fluid) or control group (counseling alone, provided by trial nurses over 6 visits, as well as a $50 voucher). Participants self-collected urine to bring to a 6-month follow-up visit for biochemical confirmation of abstinence by measurement of anabasine, a tobacco alkaloid not present in e-cigarettes. 

Who were the patients? 1,246 participants (mean age 38, half were female) who smoked at least 5 cigarettes a day for at least the past year and wanted to quit were randomized. Among the included patients, 85% had at least one prior attempt to quit. Patients who had used NRT or e-cigarettes regularly in the past 3 months were excluded.  

Top-line results: This was a positive study. Biochemically validated, continuous abstinence from smoking at 6 months was more common in the intervention group: 28.9% versus 16.3% (absolute difference: 12.6%; adjusted relative risk: 1.77). However, individuals in the intervention group were also less likely to be abstinent from all nicotine products at 6 months (20% versus 34%); minor adverse adverse events were also more common. 

Learning points & limitations: This was a well-done study without clear sources of chance (the primary outcome and protocol were unchanged); or bias (there is no overt evidence of pre- or post-randomization selection bias) that could explain the positive outcome. Follow-up duration was relatively short, so questions about the consequences of long-term e-cigarette use remain.

Bottom line/Hotcakes rating

Further reading:

Hotcake #2: Gabapentinoids and COPD exacerbations (Rahul)

Rahman AA, et al. Gabapentinoids and Risk for Severe Exacerbation in Chronic Obstructive Pulmonary Disease: A Population-Based Cohort Study. Ann Intern Med. 2024 Feb;177(2):144-154. doi: 10.7326/M23-0849. Epub 2024 Jan 16. PMID: 38224592. 

What was the research question? Is gabapentinoid use (pregabalin or gabapentin) associated with hospitalization for COPD exacerbation?

Why is this study important? Gabapentinoids are viewed as safer than opioids, and as a result, off-label use is common and increasing. In the 2010s, case reports of severe and fatal respiratory depression associated with gabapentinoids prompted the US FDA to issue a safety warning advising caution in people with lung disease. 

How was the study done? In this retrospective cohort study, patients with COPD in a large health insurance database in Quebec, Canada who were prescribed gabapentinoids from 2001 – 2021 were identified and compared with controls who were not prescribed gabapentinoids. Propensity score matching and an active comparator / new user design were used to ensure patients compared were similar in other ways other than gabapentinoid receipt. Patients with COPD were identified using outpatient prescriptions, and hospitalizations were identified by ICD9 codes.

Who were the patients? Just over 13,000 patients receiving gabapentinoids for epilepsy, neuropathic pain, or other chronic pain were included and matched 1:1 to controls. Mean age was in the mid-70s, and medical comorbidities and polypharmacy were very common: Approximately 1 in 3 patients were prescribed opioids, and 1 in 2 were prescribed benzodiazepines. 

Top-line results: This was a positive study: over a mean of 1.5 years of follow-up, compared with non-use, gabapentinoid use for any indication was associated with a ~40% increased risk of hospitalization for COPD exacerbation (hazard ratio of 1.39, or an excess of ~7 hospitalizations per 100 patients per year). 

Learning points & limitations: The new-user, active comparator design limits confounding by indication and is comparable to an intention-to-treat analysis of an RCT, but like all observational studies, this one is still vulnerable to residual confounding (for example, data on current or  former smoking was not available). Misclassification of the exposure was likely, as prescribing information was only available for 40% of the Quebec population, but I would expect this to bias towards a null finding.    

Bottom line: Avoid gabapentinoids in COPD due to questionable benefit and likely harm.  

Hotcakes rating: 4/5

Further reading:

Hotcake #3: Lidocaine for Neck Pain (Watto)

Cohen SP, et al. Multicenter, Randomized, Placebo-controlled Crossover Trial Evaluating Topical Lidocaine for Mechanical Cervical Pain. Anesthesiology. 2024 Mar 1;140(3):513-523. doi: 10.1097/ALN.0000000000004857. PMID: 38079112. 

What was the research question? Are lidocaine patches better than placebo for chronic mechanical neck pain in adult patients?

Why is this study important? There are no approved medical treatments for neck pain and everyone loves the idea of lidocaine patches. A few small studies have suggested topical lidocaine may help mechanical neck pain.

How was the study done? In this randomized, blinded, placebo-controlled cross-over trial, 76 patients in the United States were randomized 1:1 to a placebo-lidocaine sequence or to a lidocaine-placebo sequence (with a 1 week washout period in between). The placebo patches were reportedly “identical in dimensions, texture, and smell.” It was analyzed via “intention-to-treat without missing data imputation”, but it seemed like more of a per-protocol analysis because not all 38 patients contributed data to the phase 1 or phase 2 analysis. 

Who were the patients? Median age 54, 2/3rd female. No inciting event was present in 65%, and the median duration of pain was 5 years. Half of the patients had concomitant back pain, and two-thirds had concomitant depression or anxiety. 

Top-line results: This was a negative trial of lidocaine patches, a “topical system containing” 1.8% lidocaine, vs identical placebo patches because they failed to prove a between-group difference of at least 1 point on a 10-point neck pain score. They observed a median reduction in average neck pain score of -1.0 (interquartile range, -2.0, 0.0) for the lidocaine phase versus -0.5 (interquartile range, -2.0, 0.0) for placebo treatment (P = 0.17). 

Learning points & limitations: This study used a newer, thinner, lidocaine “topical system” with improved biopharmaceutical efficiency, meaning these 1.8% lidocaine patches can deliver bioequivalent plasma levels to 5% lidocaine patches despite containing less lidocaine per gram adhesive. The lead author received funding from Scilex, the manufacturer of the patches. This was a well-done negative study that was unlikely to be underpowered despite not reaching target enrollment.   

Bottom line/Hotcakes rating: I give this 3.5 Hotcakes. Mechanical neck pain needs a mechanical solution and lidocaine patches should be reserved for neuropathic pain. 

Further reading:

  • Narrative review of 5% lidocaine for chronic low back pain. Santana, 2020 
  • Review of topical lidocaine for various types of chronic pain Voute, 2021
  • More information on the 1.8% lidocaine patch Gudin, 2020.

Hot take #1 Cdiff antibiotic hierarchy (Rahul)

Miller AC, et al; CDC MInD-Healthcare Group. Comparison of Different Antibiotics and the Risk for Community-Associated Clostridioides difficile Infection: A Case-Control Study. Open Forum Infect Dis. 2023 Aug 5;10(8):ofad413. doi: 10.1093/ofid/ofad413. PMID: 37622034; PMCID: PMC10444966. 

Summary:Prior studies on the strength of association between receipt of various antibiotics and C. diff infection (CDI) have been limited by small size and inconsistent exposure windows. This study was a matched case-control study using a nationally representative database of insurance claims for Medicare and Medicaid from 2001 – 2021 that sought to estimate the association between exposure to 27 different outpatient antibiotics and CDI. Eligible patients had no inpatient stay in the preceding 3 months (the outcome was limited to community-acquired CDI to isolate the risk attributable to antibiotics). Controls were other people in the database, matched on age, gender, Medicaid status, with the same index date assigned as people who received antibiotics. About 150,000 cases and 800,000 controls (matched 5:1) were included.

Bottom line: There is a lot of variation not only between but also WITHIN antibiotic classes – so it is too simplistic to say “fluoroquinolones are worse than cephalosporins,” for example – the details matter! Here’s the general takeaway for risk categories for CDI:

  1. Highest risk (ORs of 10-20): clindamycin and later-generation cephalosporins
  2. Moderate risk (ORs of 5-10): fluoroquinolones and penicillins
  3. Lower risk (ORs of 1-3): sulfonamides and macrolides
  4. No risk (ORs ~1 or less): tetracyclines

Hot take #2 GLP1 News (Watto)

Whitley HP, Trujillo JM, Neumiller JJ. Special Report: Potential Strategies for Addressing GLP-1 and Dual GLP-1/GIP Receptor Agonist Shortages. Clin Diabetes. 2023 Summer;41(3):467-473. doi: 10.2337/cd23-0023. Epub 2023 Apr 7. PMID: 37456085; PMCID: PMC10338283. 

Summary: There is a “budget ozempic” hack on TikTok telling people to ingest laxatives (NOTE: don’t do this!). Recently, a Curbsiders listener on Discord, Scott, alerted us that some doctors are prescribing high-dose semaglutide pens and then instructing patients to “dose by clicks” to administer smaller doses to make the pens last longer. This Reddit thread describes the practices and this doctor from Canada even has a handout with instructions for his patients! The official package insert tries to discourage counting clicks. A 2023 article by, Whitley et al, includes a table with dosing by clicks for semaglutide 0.25-0.5 mg (2 mg/3mL), 1 mg (4 mg/3mL), and 2 mg (8 mg/3mL) pens. It takes 37 clicks for a half dose and 74 clicks for a full dose, but the authors suggest that patients might target in between doses to customize titration based on side effects. It should be noted that the pens are stable for 56 days once opened and should be discarded thereafter (Whitley, 2023). **Update: After this episode aired we learned that “Dosing by clicks” works for the branded Ozempic pens, but not the Wegovy pens.**

Bottom line: We are not endorsing “dosing by clicks” and it is not something I’m talking about with my patients. However, it’s important for us as clinicians to be aware of the zeitgeist, especially when it concerns the most popular medication of all time, which is currently experiencing a major supply-demand mismatch, not to mention a huge price tag.


Links

Links are included in the show notes above.


Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

  1. Evaluate the utility of e-cigarettes for smoking cessation
  2. Discuss potential respiratory complications of gabapentinoids
  3. Determine whether or not lidocaine patches are effective for neck pain

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Ganatra RB, Williams PN, Watto MF. “#432 Hotcakes: E-cigarettes for smoking cessation, Gabapentin and COPD exacerbations, Lidocaine for neck pain, C diff risk by antibiotic type, and “dosing by clicks” for GLP1’s”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, March 27, 2024.

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Episode Credits

Written and Hosted by: Rahul Ganatra MD, MPH; Paul Williams, MD, FACP, Matthew Watto MD, FACP
Cover Art: Matthew Watto MD, FACP
Reviewer: Rahul Ganatra MD, MPH
Technical Production: Pod Paste
Showrunners: Matthew Watto MD, FACP; Paul Williams MD, FACP

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