Gabapentinoids and opioids: the added risk

A sixty-eight-year-old man arrives at the ward on the second day after a hip arthroplasty. He receives rescue morphine, a scheduled oral opioid and, since before surgery, pregabalin for the low back pain that has accompanied him for years. At the shift handover, the nursing staff comment that he "has been sleeping a lot" and that his saturation dropped during the night, returning to normal when he was woken. No one changed anything in the prescription in the last few hours. Each medication, on its own, seems reasonable. Added together, they tell another story. This text uses the combination of gabapentinoids and opioids as a clinical reasoning scenario: why the risk adds up, who is most exposed, how the prescription accumulates in a chain, how to look at non-prescribed use without judgment and how to review the medication list. The scene and the examples throughout the text are fictional and were written for teaching.

NEXO is a daily medical diagnosis game: one clinical case a day, up to six progressive clues, and ICD-10 proximity feedback across five levels.

The text also avoids being a dosing protocol. Adjustments, reductions and monitoring follow the guidelines and protocols of each service, under supervision. The focus here is the way of thinking: what questions to ask when two central nervous system depressants meet, how to weigh each patient's context and how to keep an important clue from being read as a detail. If you play the case of the day on NEXO, you will recognize the move: a clue that seems secondary can change the weight of every hypothesis.

Key points

• Gabapentin and pregabalin added to opioids increase the risk of sedation and respiratory depression, according to an FDA warning and large observational studies.
• The risk grows with advanced age, lung disease, kidney disease, higher doses and other depressants in the same prescription.
• The combination usually arises in a chain, with different prescribers, and reviewing the full list is the step that brings the pieces together.
• Non-prescribed use of gabapentinoids is more frequent among people who use opioids, and asking without judgment opens room to reduce harm.
• When the combination is necessary, the decision includes the lowest effective dose, monitoring and clear information for the person and the family.

Why two common medicines call for attention together

Gabapentin and pregabalin, the gabapentinoids, entered practice as anticonvulsants and gained ground in the treatment of neuropathic pain, fibromyalgia and other complaints. Goodman and Brett, in an analysis published in the New England Journal of Medicine, showed that prescribing grew a great deal, including for indications with limited evidence, and warned about the perception that these medicines were harmless (Goodman and Brett, 2017). That perception is part of the problem. A medicine seen as "mild" tends to be added easily and withdrawn rarely.

Opioids, in turn, depress the respiratory center in a dose-dependent way. When a gabapentinoid enters the same prescription, the sedative effect adds up. In December 2019, the Food and Drug Administration of the United States published a safety communication about serious breathing difficulty with gabapentin and pregabalin in people with risk factors, including the use of opioids and other central nervous system depressants, advanced age and lung disease. The agency advises starting with the lowest dose and monitoring the person when this combination is present (FDA, 2019).

What population studies say

Tara Gomes and colleagues conducted a nested case-control study with people using opioids in Ontario, Canada. Concomitant use of gabapentin was associated with a substantial increase in the risk of opioid-related death, and the authors recommended carefully assessing whether to maintain the combination and monitoring closely when it is necessary (Gomes and colleagues, 2017). The same group repeated the analysis with pregabalin and found a similar association with opioid-related death (Gomes and colleagues, 2018).

Observational studies have limits. People who receive both classes may have more intense pain, more diseases and more vulnerabilities. Even so, the pattern repeats across different populations and has pharmacological plausibility, and so it enters the reasoning as a signal that changes the weight of the decision. For those who reason with probabilities, the observational study adjusts the probability of harm even before any test: an older person with lung disease and both classes on the prescription starts from a higher baseline risk than a young adult with the same pair of medications. The post on pre-test probability explains this logic with other examples.

Who is most exposed: clues that change the risk

The risk of the combination varies greatly from person to person. Some clues, gathered from the FDA notice and the studies cited, increase the weight of concern:

• Advanced age, with lower respiratory reserve and greater sensitivity to sedation.
• Lung disease, such as chronic obstructive pulmonary disease, or sleep apnea.
• Reduced kidney function, since gabapentin and pregabalin are eliminated by the kidneys.
• Higher doses of gabapentinoid or opioid, or recent increases.
• Other depressants on the prescription, such as benzodiazepines, hypnotics, sedative antipsychotics and alcohol.
• The immediate postoperative period, when rescue opioids are added to scheduled ones.

The table organizes the reasoning by context, to remind us that the same pair of medications carries different weights depending on the scenario.

Context	What increases the risk	Question that helps
Postoperative	Rescue opioid added to the scheduled one and gabapentinoid in the analgesic regimen	Who reviewed the total sum of depressants in the last hours?
Older person in the outpatient clinic	Different prescribers, reduced kidney function, falls	Was the gabapentinoid dose adjusted to kidney function?
Chronic pain with long-standing opioid	Gradual increases of both classes over the years	Does the original indication for the gabapentinoid still exist?
Treatment with an opioid agonist	Non-prescribed use of gabapentinoid to boost the effect	Does the person know that the combination increases the risk of overdose?
Lung disease or sleep apnea	Lower respiratory reserve	Is there adequate monitoring for tonight?

The postoperative period as a risk laboratory

Gabapentinoids have become part of many multimodal analgesia regimens, with the intention of sparing opioids. Krista Bykov and colleagues analyzed surgical admissions in the United States and found an association between the use of gabapentinoids with opioids and a higher risk of overdose and other opioid-related adverse events, with a low absolute risk (Bykov and colleagues, 2020). In laparoscopic surgeries, Cavalcante and colleagues observed an association between gabapentin and postoperative respiratory depression and suggested reducing intraoperative opioids and increasing vigilance, especially in older people (Cavalcante and colleagues, 2017).

The lesson for reasoning is twofold. The absolute risk may be small for a young and healthy person, and relevant for someone who adds age, lung disease and high doses. And timing matters: the first nights after surgery concentrate rescues, deep sleep and less observation.

The chain prescription

Rarely does someone decide, in a single consultation, to prescribe an opioid and a gabapentinoid together for a frail person. More often the sum happens little by little. The neurologist starts gabapentin for a neuropathy. Years later, the orthopedist prescribes an opioid after a fracture. The clinician renews both. During hospitalization, the anesthesiologist adds pregabalin to the analgesic regimen. Each decision makes sense in its context, and nobody looks at the sum.

Rochon and Gurwitz described the prescribing cascade: an adverse effect is read as a new problem and receives another medication (Rochon and Gurwitz, 1997). With gabapentinoids, the cascade appears when dizziness becomes a workup for vertigo, peripheral edema gets a diuretic and drowsiness is attributed to age. At each step, the question that breaks the chain is simple: does any medication in use explain this finding?

Biases that keep the combination going

Pat Croskerry describes cognitive shortcuts that affect clinical decisions, among them anchoring, premature closure and the tendency to keep what is already underway (Croskerry, 2003). In the gabapentinoid scenario, some appear often:

1. Bias of harmlessness. The gabapentinoid is seen as a mild medication, and the added risk goes unnoticed.
2. Anchoring on pain. The pain complaint supports each dose increase, without reassessing the effect obtained.
3. Fragmentation. Each prescriber takes care of their part and assumes another has reviewed the whole.
4. Attribution to age. Drowsiness, falls and confusion are read as aging, and the medication list stays out of it.
5. Label in nonprescribed use. The person who asks for more gabapentin is seen as "drug seeking", and the conversation about risk is lost.

The post on examples of heuristics in clinical reasoning organizes these shortcuts and shows when they help and when they get in the way.

Nonprescribed use: asking without judgment

Gabapentin and pregabalin have potential for nonprescribed use, especially in people who use opioids. The systematic review by Rachel Smith and colleagues found misuse of gabapentin in several countries, with populations that use substances at special risk, and reports of subjective effects that resemble opioids, benzodiazepines and psychedelics (Smith and colleagues, 2016). The review by Evoy and colleagues reached a similar conclusion and recommended that prescribers know the populations at higher risk and monitor for signs of misuse (Evoy and colleagues, 2017).

In the United Kingdom, concern about misuse and about deaths involving gabapentinoids led to the reclassification of gabapentin and pregabalin as class C controlled substances from April 2019 (UK Government, 2018). The measure shows that the risk was recognized by regulators, and clinical reasoning remains individual.

How to open the conversation

Asking about nonprescribed use calls for the same stance as any conversation about substances. Some phrases help keep the door open:

• "Many people use gabapentin or pregabalin in ways that differ from the prescription. Does that happen with you?"
• "When you use it together with the opioid or with methadone, what do you feel?"
• "Can I explain why this combination increases the risk of stopping breathing?"
• "What would help you use it more safely in the coming days?"

The language chosen changes how the team sees the person. The post on stigma and language shows how labels change conduct, and the post on motivational interviewing brings techniques for conversations in which the person is still deciding what to do.

Harm reduction in practice

For those who use gabapentinoids outside the prescription together with opioids, the conversation can include information about the added risk, about using less when there is another substance, about avoiding using alone and about having naloxone nearby. This logic follows the reasoning of the post on harm reduction beyond all or nothing: every step that lowers the risk counts, even if use continues.

Opioid agonist treatment and gabapentinoids

People in treatment with methadone or buprenorphine sometimes also receive gabapentinoids, for neuropathic pain, anxiety or other indications. The presence of a scheduled opioid agonist weighs on the decision, and treatment of opioid use disorder remains the priority. Withdrawing or reducing the agonist to "make room" for the gabapentinoid is rarely the best choice, because agonist treatment protects against overdose.

The decision usually comes down to reassessing the indication for the gabapentinoid, using the lowest effective dose, considering alternatives for the symptom and combining monitoring. When choosing between methadone and buprenorphine, the respiratory depression profile enters the conversation, and the post on buprenorphine or methadone organizes this shared decision. When buprenorphine is going to be started in someone already using other depressants, the post on precipitated withdrawal at the start of buprenorphine helps to think through the timing of induction.

What to record

When the combination is maintained, a clear record helps the next professional: the indication for each medication, the total dose, the risk factors considered, the guidance given to the person and who will reassess. This record breaks the chain of automatic renewals.

At transitions between services, the risk of losing information increases. A person discharged from hospital with new pregabalin, a short-acting opioid and the usual agonist may arrive at the community pharmacy and the outpatient clinic with no one knowing which medication is temporary. Writing in the discharge summary what should be stopped, when and by whom helps prevent a prescription meant for a few days from becoming long-term use. The same logic applies to admission: checking with the person and the family what they actually take at home, including what is not on the prescription, often reveals the missing piece.

Medication list review: a roadmap

Medication review is the step that brings together the pieces scattered across a chain prescription. Ian Scott and colleagues proposed a stepwise deprescribing process: list all medications, estimate the risk of harm, assess whether each still has benefit, prioritize those that can be reduced and follow the person during the change (Scott and colleagues, 2015). The roadmap applies well to the combination of gabapentinoids and opioids.

Questions for each item on the list

In practice, the review can follow a few questions:

1. What was the original indication for the gabapentinoid, and does it still exist?
2. Was there a measurable benefit in pain or function?
3. Is the dose adjusted to current kidney function?
4. How many central nervous system depressants are on the list, including those used occasionally?
5. Does the person use alcohol or substances outside the prescription?
6. Who prescribed each medication, and who will follow the change?

The 2022 Centers for Disease Control and Prevention guideline for opioid prescribing recommends caution when combining opioids with other central nervous system depressants and reinforces ongoing assessment of risks and benefits (Dowell and colleagues, 2022). The guideline also reminds us that changes should be made with the person, not for them.

Reducing with care

The gabapentin and pregabalin labels advise reducing gradually, over at least a week, and the pregabalin label describes insomnia, nausea, headache, anxiety and sweating after abrupt discontinuation; in people with epilepsy, rapid withdrawal can precipitate seizures (FDA, Neurontin label; FDA, Lyrica label). The pace follows the service protocol and the person's response. When a benzodiazepine is on the same list, it is worth remembering that reducing it carries its own risks, and the post on this topic in the series covers pace and shared decision.

Sedation and breathing: what to watch for

When the combination exists, the team needs to know what to watch for. Sedation usually precedes respiratory depression, and so the level of consciousness is a clue that appears early. A person who sleeps too much, responds slowly or drifts back to sleep mid-conversation deserves attention before saturation falls.

Some bedside findings help decide when to act: drowsiness greater than expected for the time and context, slurred speech or difficulty keeping up the conversation, low respiratory rate or pauses observed during sleep, and a drop in saturation that improves when the person is woken. This last finding deserves emphasis, because improvement on waking can reassure the team precisely when the risk is greatest. The person falls back asleep, the stimulation stops and breathing drops again. In people with sleep apnea, the pattern can overlap with that of the underlying disease and confuse the reading.

Another trap is attributing drowsiness only to post-operative fatigue or a bad night's sleep. Before accepting that explanation, it is worth checking the time of the last rescue dose, the total dose received in recent hours and whether any new sedative entered the prescription. The reasoning is the same as for any differential: the most comfortable explanation must be tested against the others.

When opioid overdose is suspected, the decision about naloxone follows its own reasoning, which the post on opioid overdose and the naloxone decision develops in detail. It is worth remembering that naloxone reverses the opioid component, and the effect of the gabapentinoid continues, which reinforces monitoring after reversal.

Education for the person and the family

Discharge is an important moment. The person and the family can receive information about signs of excessive sedation, about avoiding alcohol and other sedatives, about the importance of following the prescribed dose and about when to seek help. In higher-risk settings, having naloxone at home and knowing how to use it is part of the conversation.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues. You propose a diagnosis by searching for the ICD-10 code and receive proximity feedback at five levels, which shows whether the guess landed on the exact code, the same category, the same group, the same chapter or a different chapter. This format speaks to the theme of this text: a medication listed in passing can be the clue that explains the picture, and the feedback shows whether you gave it the right weight.

To use the case of the day as training, try three habits. Before each guess, list the medications mentioned and ask whether their sum explains the clue. When the answer seems obvious, write down the second most likely hypothesis. After the result, note which clue you underestimated.

Three exercises with cases

Add up the depressants. In each case, count how many medications or substances can depress consciousness or breathing.

Look for the chain. Identify who prescribed each medication and at what moment, and where the review could have interrupted the sum.

Rewrite the record. Take a chart sentence with a label, such as "seeking drugs", and rewrite it in person-centered language.

The post on learning based on clinical cases shows why training with cases fixes this type of decision, and the post on calibration of confidence in diagnosis helps you record how much you trust each hypothesis.

The limits of use of the game are described on the NEXO economy page. If you research teaching of clinical reasoning, the page for researchers explains how to get in touch. Professionals who write or review cases find information in curation and in creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Can gabapentin and an opioid be used together?

They can, when the benefit justifies it and there is care. The FDA advises starting with the lowest dose and monitoring the person when this combination is present (FDA, 2019).

Does pregabalin carry the same risk as gabapentin?

The studies by Gomes and colleagues found an association with opioid-related death for both, with similar designs (Gomes and colleagues, 2018).

Who is at greater risk with the combination?

Older people, people with lung disease, sleep apnea, reduced kidney function, higher doses or other depressants in the prescription concentrate the greatest risk.

How to ask about non-prescribed use of gabapentin?

With open, normalizing questions, explaining the reason for the question and offering information about the added risk. The conversation works better when the person perceives that the goal is safety.

Does naloxone reverse the effect of the gabapentinoid?

Naloxone reverses the opioid component. Sedation from the gabapentinoid may continue, and that is why observation after reversal is important.

Should the gabapentinoid be withdrawn from every patient using an opioid?

The decision is individual and starts with reviewing the indication, the benefit and the risk factors. When reduction is chosen, it is usually gradual and agreed with the person.

Final checklist

• I listed all central nervous system depressants in use, including alcohol and non-prescribed use.
• I reviewed the indication and the benefit of the gabapentinoid.
• I checked the dose against kidney function.
• I assessed age, lung disease and sleep apnea.
• I combined the lowest effective dose with adequate monitoring.
• I talked with the person and the family about signs of sedation and about naloxone.
• I recorded the decision and who will reassess.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. Bykov K, Bateman BT, Franklin JM, et al. Association of Gabapentinoids With the Risk of Opioid-Related Adverse Events in Surgical Patients in the United States. JAMA Netw Open. 2020. PMID 33372975.
2. Cavalcante AN, Sprung J, Schroeder DR, Weingarten TN. Multimodal Analgesic Therapy With Gabapentin and Its Association With Postoperative Respiratory Depression. Anesth Analg. 2017. PMID 27984223.
3. Croskerry P. The importance of cognitive errors in diagnosis and strategies to minimize them. Acad Med. 2003. PMID 12915363.
4. Dowell D, Ragan KR, Jones CM, et al. CDC Clinical Practice Guideline for Prescribing Opioids for Pain, United States, 2022. MMWR Recomm Rep. 2022. PMID 36327391.
5. Evoy KE, Morrison MD, Saklad SR. Abuse and Misuse of Pregabalin and Gabapentin. Drugs. 2017. PMID 28144823.
6. FDA. FDA warns about serious breathing problems with seizure and nerve pain medicines gabapentin and pregabalin. Drug Safety Communication. 2019. fda.gov.
7. FDA. Lyrica (pregabalin) prescribing information. DailyMed. dailymed.nlm.nih.gov.
8. FDA. Neurontin (gabapentin) prescribing information. DailyMed. dailymed.nlm.nih.gov.
9. Gomes T, Greaves S, van den Brink W, et al. Pregabalin and the Risk for Opioid-Related Death: A Nested Case-Control Study. Ann Intern Med. 2018. PMID 30140853.
10. Gomes T, Juurlink DN, Antoniou T, et al. Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Med. 2017. PMID 28972983.
11. Goodman CW, Brett AS. Gabapentin and Pregabalin for Pain: Is Increased Prescribing a Cause for Concern? N Engl J Med. 2017. PMID 28767350.
12. UK Government. Pregabalin and gabapentin to be controlled as Class C drugs. 2018. gov.uk.
13. Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: the prescribing cascade. BMJ. 1997. PMID 9366745.
14. Scott IA, Hilmer SN, Reeve E, et al. Reducing inappropriate polypharmacy: the process of deprescribing. JAMA Intern Med. 2015. PMID 25798731.
15. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction. 2016. PMID 27265421.