A new study reveals a significant and concerning trend: the co-prescribing of gabapentinoids alongside long-term opioid therapy has surged over the past decade, increasing from 47% in 2015 to 58.7% in 2023. This rise occurs despite a specific 2019 warning from the U.S. Food and Drug Administration (FDA) cautioning against the serious respiratory depression risks associated with combining gabapentinoids with opioids and other central nervous system (CNS) depressants. The findings, published in a JAMA research letter by researchers from the University of Michigan, highlight a growing patient safety issue, particularly as the demographic of individuals receiving long-term opioid therapy is simultaneously trending older, with nearly half of these patients now covered by Medicare.
The study’s authors, including Thuy Nguyen, PhD, Assistant Professor of Health Management and Policy at the University of Michigan’s School of Public Health, emphasized the heightened vulnerability of older adults to the adverse effects of polypharmacy – the concurrent use of multiple medications. "Because older adults are at higher risk of adverse events from polypharmacy, the increased rates of coprescribing, particularly with gabapentinoids, raises additional safety concerns," Dr. Nguyen stated. This demographic shift, where the average age of patients on long-term opioids rose from 52.5 years in 2015 to 60.5 years in 2023, compounds the inherent risks, making the unheeded FDA warnings a critical public health challenge.
Understanding Gabapentinoids and Their Role in Pain Management
Gabapentinoids, a class of nerve medications, primarily include gabapentin (marketed as Neurontin and its generics) and pregabalin (marketed as Lyrica and its generics). Initially developed to treat epilepsy and neuropathic pain, these drugs work by modulating neurotransmitter activity in the brain. Gabapentin, first approved in 1993, and pregabalin, approved in 2004, quickly gained traction beyond their initial indications. They are now widely prescribed off-label for a broad spectrum of conditions, including various chronic pain syndromes, anxiety, and insomnia. The term "off-label" refers to the practice of prescribing a drug for an unapproved indication, dosage, or patient population. While legal and often clinically appropriate, the sheer volume of off-label prescribing for gabapentinoids, estimated to be as high as 95% of all prescriptions in some studies, raises questions about the evidence base for their widespread use in certain contexts and the adequacy of post-market surveillance.
The surge in gabapentinoid prescribing, particularly for pain, has been influenced by several factors. In the wake of the escalating opioid crisis, which gained national attention in the mid-2010s, healthcare providers faced intense pressure to reduce opioid prescriptions and seek alternative pain management strategies. Gabapentinoids, perceived by some as having a lower risk of addiction and fewer severe side effects compared to opioids, emerged as a seemingly safer alternative or an adjunct therapy to reduce opioid dosages. This perception, however, overlooks the significant risks when gabapentinoids are combined with other CNS depressants, a danger explicitly highlighted by the FDA.
A Timeline of Warnings and Prescribing Trends
The journey towards the current state of increased co-prescribing is marked by specific regulatory actions and evolving clinical practices:
- Early 2000s – 2010s: Gabapentinoids see increasing off-label use for various pain conditions. Their "non-opioid" nature makes them attractive alternatives or complements in pain management.
- 2010: Gabapentin prescriptions begin a sharp upward trajectory, nearly tripling by 2024. This period coincides with growing awareness and concern over the opioid epidemic.
- 2015: The baseline year for the University of Michigan study. At this point, 47% of patients on long-term opioid therapy were also receiving gabapentinoids. The average age of these patients was 52.5 years. The number of U.S. patients on long-term opioid therapy (at least 90 days) stood at 5.6 million, with an average daily dose of 47.9 morphine milligram equivalents (MME).
- 2016: The Centers for Disease Control and Prevention (CDC) issues its Guideline for Prescribing Opioids for Chronic Pain. This influential guideline recommends caution when doses exceed 50 MME per day and emphasizes non-opioid therapies, further incentivizing the use of drugs like gabapentinoids.
- December 2019: The FDA issues a significant safety warning. The agency mandated new warnings be added to the prescribing information for gabapentin (Neurontin, Gralise) and pregabalin (Lyrica, Lyrica CR). The warning explicitly stated that serious breathing problems can occur in patients using gabapentinoids who also take opioids or other CNS depressants, or those with underlying respiratory risk factors such as chronic obstructive pulmonary disease (COPD) or advanced age. The FDA underscored that respiratory depression could lead to a fatal overdose. This warning was a direct response to post-marketing reports and clinical data indicating a clear risk.
- 2023: The study’s end point. Co-prescribing of gabapentinoids with long-term opioids climbed to 58.7%. The average patient age increased to 60.5 years. The number of patients on long-term opioid therapy had decreased to approximately 4.2 million, a 24.3% reduction from 2015, with the average daily opioid dose falling to 38.6 MME, aligning with CDC guidelines.
- 2024: Gabapentin becomes the fifth most prescribed drug in the U.S., with over 15.5 million Americans prescribed the drug. This surge in overall prescribing volume further amplifies the concerns surrounding its co-administration with opioids.
Supporting Data and Shifting Prescribing Landscapes
The study’s granular data paints a comprehensive picture of evolving prescribing patterns. While the co-prescribing of gabapentinoids with opioids increased, other forms of polypharmacy involving opioids saw different trends. The co-prescribing of long-term opioids with benzodiazepines, another class of CNS depressants with well-documented respiratory risks, notably declined from 43.8% in 2015 to 33.5% in 2023. This reduction suggests that efforts to curb benzodiazepine-opioid co-prescribing, which have been a focus of regulatory and clinical warnings for years, may be yielding some success. Conversely, co-prescribing for stimulants with opioids saw a slight increase, from 5.9% to 6.7% over the same period, indicating a complex and varied landscape of medication combinations.
The decline in long-term opioid use and the average daily opioid dose are positive outcomes, reflecting the impact of federal and state guidelines aimed at mitigating the opioid crisis. The reduction in the number of patients on long-term opioid therapy from 5.6 million to 4.2 million, alongside a decrease in average daily MME from 47.9 to 38.6, suggests that clinicians are generally adhering to recommendations for lower opioid dosages. However, this progress is overshadowed by the concurrent rise in gabapentinoid co-prescribing, indicating a potential "substitution" effect or an unintended consequence where one risk factor is managed while another emerges or intensifies.
The demographic shift towards an older patient population on long-term opioids, with 48.7% covered by Medicare, adds another layer of complexity. Older adults are inherently more susceptible to adverse drug events due to age-related physiological changes, multiple comorbidities, and often, a higher burden of polypharmacy. Their metabolism of drugs can be slower, increasing drug accumulation and the risk of side effects. Furthermore, they are at higher risk of falls, cognitive impairment, and delirium, all of which can be exacerbated by CNS depressants like opioids and gabapentinoids.
Official Responses and the Call for Action
While the original article does not provide direct "official responses" from regulatory bodies or professional organizations to this specific study, the implications necessitate a proactive stance.
- Food and Drug Administration (FDA): The FDA’s 2019 warning serves as a foundational "official response." The findings of this JAMA study reinforce the urgency and continued relevance of that warning. It is highly probable that the FDA would reiterate its recommendations for careful patient selection, dosage adjustments, and thorough monitoring, especially for older adults and those with respiratory issues. The agency may also consider further educational campaigns for prescribers.
- Medical Professional Organizations: Groups such as the American Medical Association (AMA), American Academy of Pain Medicine (AAPM), and the American Geriatrics Society (AGS) would likely respond by emphasizing the need for enhanced clinician education on safe prescribing practices, particularly regarding polypharmacy in older adults. They might call for updated clinical guidelines that specifically address the risks of gabapentinoid-opioid combinations and advocate for comprehensive pain management strategies that integrate non-pharmacological approaches. The AGS, in particular, has long championed the "deprescribing" movement, aiming to reduce unnecessary medications in older adults.
- Medicare and Insurance Providers: Given the high percentage of Medicare beneficiaries affected, the Centers for Medicare & Medicaid Services (CMS) and private insurers have a vested interest in these findings. Increased adverse events lead to higher healthcare costs (hospitalizations, emergency visits). They might intensify their drug utilization review (DUR) programs, implement prior authorization requirements for certain high-risk combinations, or develop quality measures to monitor and reduce inappropriate co-prescribing.
- Policymakers: Legislators and public health officials might consider measures to improve prescription drug monitoring programs (PDMPs) to better track gabapentinoid prescriptions alongside opioids, similar to how they track other controlled substances. Funding for research into non-pharmacological pain treatments and multimodal clinics could also be prioritized.
Broader Impact and Implications
The implications of this escalating co-prescribing trend are far-reaching, affecting patient safety, healthcare system burden, and the very philosophy of pain management.
- Enhanced Patient Safety Risks: Beyond respiratory depression, the combination of gabapentinoids and opioids can significantly increase the risk of other serious adverse events. Both drug classes are known to cause dizziness, sedation, and impaired coordination. Their synergistic effects amplify these risks, leading to a higher incidence of falls, particularly dangerous for older adults who are more prone to fractures and associated complications. Cognitive impairment, including brain fog and confusion, can also be worsened, impacting daily functioning and quality of life. The potential link between gabapentin use and an increased risk of dementia, as suggested by previous studies, adds another layer of long-term concern, especially for an aging population.
- The "Prescribing Cascade": A critical consequence of polypharmacy is the "prescribing cascade." This phenomenon occurs when an adverse drug reaction is misdiagnosed as a new medical condition, leading to the prescription of additional, often unnecessary, medications. For instance, gabapentin’s side effects like dizziness, fatigue, or anxiety could be mistaken for new symptoms, prompting a doctor to prescribe another drug to "treat" these side effects, rather than recognizing gabapentin as the root cause and considering its discontinuation. This cascade not only increases the number of medications a patient takes, raising the risk of further adverse events and drug-drug interactions, but also adds to the healthcare cost burden and patient inconvenience.
- Challenges in Pain Management Philosophy: The increase in gabapentinoid-opioid co-prescribing reflects a persistent challenge in chronic pain management. While there is a clear imperative to reduce opioid reliance, clinicians are often left with limited effective alternatives for severe, persistent pain. Gabapentinoids are often employed in an attempt to potentiate opioid analgesia or reduce overall opioid dosage, but this strategy, as the FDA warning underscores, comes with its own set of risks. The study’s senior author, Pooja Lagisetty, MD, Associate Professor of Internal Medicine at the University of Michigan Medical School, rightly points out the widespread nature of chronic pain and the pressing need for better treatment models. "With almost 5 million Americans on long-term prescription opioids for chronic pain, and likely millions more who are taking shorter courses of prescription opioids for acute pain, most clinicians are likely to care for someone using prescription opioids for pain, highlighting the pressing importance for investing in better treatment models for pain," Dr. Lagisetty observed. This underscores the systemic failure to adequately invest in and disseminate comprehensive, multimodal pain management approaches that go beyond pharmacotherapy.
- Healthcare System Burden and Costs: Adverse drug events from polypharmacy contribute significantly to healthcare utilization and costs. Hospitalizations due to falls, respiratory depression, or severe drug interactions place a strain on emergency departments and inpatient facilities. The management of these complications, including diagnostic tests, specialist consultations, and extended hospital stays, represents a substantial financial burden on patients, insurers, and the healthcare system as a whole.
- Regulatory and Monitoring Gaps: The continued increase in gabapentinoid-opioid co-prescribing despite explicit FDA warnings suggests potential gaps in the dissemination and adherence to regulatory guidance. While the FDA issues warnings, ensuring their practical implementation at the point of care across millions of patient encounters remains a formidable challenge. This highlights the need for more robust post-marketing surveillance, improved integration of drug safety alerts into electronic health records, and continuous medical education for prescribers. The fact that gabapentin, despite its known risks and high rates of off-label use, has become the fifth most prescribed drug in the U.S. also points to a broader systemic issue regarding drug promotion, physician education, and patient demand for perceived "non-addictive" pain solutions.
In conclusion, the escalating trend of gabapentinoid and opioid co-prescribing, particularly among an aging patient population, represents a critical public health concern that demands immediate attention. While efforts to curb opioid use have shown success, the simultaneous rise in high-risk polypharmacy indicates an unintended consequence that could undermine patient safety. Addressing this complex issue will require a multi-faceted approach, including intensified prescriber education, stronger enforcement of prescribing guidelines, improved drug monitoring systems, and a concerted investment in developing and disseminating safer, more effective, and comprehensive strategies for chronic pain management. The ultimate goal must be to ensure that patients receive effective pain relief without inadvertently exposing them to preventable and potentially life-threatening risks.