Iatrogenic Origin of Addiction From, and Dependence On, Non‑Opioid Medications Used in Pain Care

Everyone knows about the opioid crisis. But risk of addiction to non-opioid pain killers is real. HHS and MAHA need to address medicine-induced harm in a serious way. This is a great place to start.

The U.S. intelligence community has just assisted the Mexican government in a military operation against a Mexican drug cartel. It’s about they join in the fight against illegal drug prescription and over-prescription of pain medications.

Many people assume that only opioid pain medicines can cause dependence. In reality, several non-opioid medications commonly used in pain care can also lead to physical dependence, withdrawal symptoms, or addiction-like patterns. These effects happen through different biological pathways but can lead to the same outcome: the body adapts to the medication, symptoms return when it is stopped, and patients may feel unable to discontinue it—even when harms begin to outweigh benefits.

Drugs such as benzodiazepines and prescription sleep medications can cause tolerance and withdrawal, including serious complications like seizures in severe cases. Gabapentin and pregabalin, widely used for nerve pain, have emerging evidence of misuse and can increase breathing risks when combined with other sedating drugs. Some antidepressants prescribed for pain can produce difficult discontinuation symptoms that are often mistaken for relapse of the original condition. Dopamine-acting medications can trigger impulse-control behaviors such as compulsive gambling or shopping. Long-term corticosteroid use can suppress the body’s natural hormone system, creating a form of physiologic dependence that requires careful tapering.

Other pain-adjacent medications—including certain muscle relaxants, barbiturate-containing headache products, ketamine, and even some over-the-counter sedatives—also carry dependence or misuse potential. However, national surveillance systems primarily measure “misuse” (use not directed by a doctor) and do not track physiologic dependence that develops during compliant medical treatment. As a result, the true population burden of non-opioid iatrogenic dependence remains incompletely quantified.

This report synthesizes regulatory warnings, national survey data, systematic reviews, and pharmacovigilance findings to clarify the mechanisms, risks, and clinical management considerations for non-opioid iatrogenic dependence in pain care. The evidence supports a shift from viewing dependence as a moral failing to recognizing it as a predictable pharmacologic effect under certain exposure conditions—one that requires informed prescribing, patient counseling, careful monitoring, and structured tapering when discontinuation is indicated. Future reports will focus on integrative approaches to mental health that provide alternatives to heavy pharmacologic means of pain management and a policy priority report tailored to effect action on HHS agency and the practice of pain management medicine.

Non‑opioid pharmacotherapy in pain care can generate iatrogenic dependence and addiction‑like outcomes through multiple mechanisms that converge on the same clinical endpoint: tolerance, withdrawal, and persistent continuation despite harm.¹,² Benzodiazepines and Z‑drugs produce GABA‑A–mediated dependence with seizure‑risk withdrawal in severe cases and predictable diagnostic “mirroring” (withdrawal insomnia/anxiety misread as relapse).²–⁴ Gabapentinoids show emerging, population‑heterogeneous misuse and withdrawal syndromes, with elevated harm risk in polysedation contexts and in patients with prior substance use vulnerability.⁵–⁷ Antidepressants used for neuropathic pain (especially short half‑life SSRIs/SNRIs) can produce clinically significant discontinuation syndromes that resist simplistic “non‑addictive” labeling despite limited classic reinforcement.⁸,⁹ Dopamine agonists can induce pharmacologic behavioral addictions (impulse control disorders) via dopaminergic stimulation.¹⁰ Corticosteroids drive physiologic dependence through HPA axis suppression and a withdrawal syndrome that overlaps inflammatory flare and adrenal insufficiency.¹¹,¹² Additional pain‑adjacent agents with dependence liabilities include carisoprodol (Schedule IV), butalbital combinations (dependence plus medication‑overuse headache feedback), ketamine (abuse liability), and OTC sedatives/dissociatives such as diphenhydramine and dextromethorphan.¹³–¹⁸ U.S. surveillance (NSDUH) captures prescription “misuse” for several categories but misses key classes (gabapentinoids, antidepressants, corticosteroids) and does not measure physiologic dependence directly.¹⁹

Methods

This report prioritized primary U.S. surveillance and regulatory sources— NSDUH (national probability survey), regulatory safety communications from , and scheduling actions from —plus pharmacovigilance and systematic evidence streams (WHO signal detection and European ADR reports) associated with and EudraVigilance/FAERS analyses.¹⁹–²¹ PubMed‑indexed systematic reviews/meta‑analyses and major guidelines anchored the class‑level synthesis, including the benzodiazepine tapering guideline, the 2024 antidepressant discontinuation meta‑analysis, and HPA‑axis guidance from and .²,⁸,¹¹ Searches targeted English‑language sources from 2000–2026; this synthesis treats rare‑agent prevalence estimates as unknown unless a population denominator exists.¹⁹–²¹ Because pharmacovigilance lacks denominators and carries reporting bias, ADR signals here support plausibility and risk characterization but cannot establish incidence.²⁰,²¹

Epidemiology

Iatrogenic addition occurs when a patient becomes addicted to prescription drugs while under the care of a doctor. This is different from individual cases of misuse without addiction, or addiction that occurs due to illicit (stolen) recreational use of pharmaceutical drugs.

NSDUH 2023 estimates 14.4 million people aged ≥12 became addicted or misused prescription “psychotherapeutics” in the past year, including 8.6 million who became addicted or misused prescription pain relievers (category dominated by opioid analgesics), 4.7 million who became addiction or misused prescription tranquilizers or sedatives (a category that includes benzodiazepines and prescription sedative‑hypnotics), and 3.9 million who became addicted or misused prescription stimulants.¹⁹ NSDUH defines misuse as use “in any way not directed by a doctor,” which captures non‑medical use and dosing beyond directions but does not measure iatrogenic physiologic dependence during compliant use, nor does it quantify withdrawal syndromes that drive continued use.¹⁹ NSDUH also omits major pain‑adjacent classes with clinically important dependence phenotypes (gabapentinoids, antidepressants used for pain, corticosteroids), creating a structural surveillance blind spot that forces clinicians to rely on guideline synthesis, post‑marketing regulatory alerts, and pharmacovigilance/case‑based evidence for those classes.⁶–⁹,¹¹,¹⁹

Drug-class synthesis

Benzodiazepines (eg, diazepam, alprazolam, clonazepam) act as positive allosteric modulators at GABA‑A receptors and rapidly suppress arousal circuitry; repeated dosing drives receptor‑level neuroadaptation that produces tolerance and physical dependence even during therapeutic use.²–⁴ Patients can develop withdrawal that includes rebound anxiety/insomnia, autonomic instability, and—when exposure is prolonged/high‑potency or discontinuation is abrupt—seizures and delirium.²,³ The clinical failure mode centers on diagnostic mirroring: withdrawal symptoms mimic the original indication, which drives dose escalation or indefinite continuation.² The ASAM‑led guideline treats abrupt discontinuation in dependent patients as unsafe and recommends individualized tapering (often starting with 5%–10% dose reductions every 2–4 weeks), with adjustment to withdrawal burden and symptom recurrence.²

Z‑drugs (zolpidem, zaleplon, eszopiclone) bind benzodiazepine receptor sites (with relative α1‑subtype preference for hypnotic effects) and can generate dependence and withdrawal insomnia despite earlier “safer” positioning.⁴,²⁰ A large EudraVigilance analysis documented substantial post‑marketing reports of abuse, dependence, and withdrawal across Z‑drugs, supporting clinically meaningful real‑world risk beyond early efficacy trials.²⁰ FDA added a boxed warning in 2019 for eszopiclone, zaleplon, and zolpidem for complex sleep behaviors that caused serious injuries and deaths, establishing a high‑consequence risk profile even at recommended doses.⁴ Withdrawal usually manifests as rebound insomnia, agitation, and autonomic symptoms; severe neuropsychiatric sequelae appear in case‑anchored literature but lack population denominators.²⁰

Gabapentinoids (gabapentin, pregabalin) bind the α2δ subunit of voltage‑gated calcium channels, reduce excitatory neurotransmission, and serve as first‑line or adjunctive therapy for several neuropathic pain syndromes.⁵,⁶ A systematic review identified gabapentin misuse prevalence near 1% in general population samples, with markedly higher prevalence in selected high‑risk cohorts (including populations with opioid abuse histories), signaling vulnerability‑weighted rather than uniform population risk.⁵ FDA warns that gabapentinoids can depress respiration, especially when combined with CNS depressants, and required label updates and abuse‑potential evaluation in response to increasing misuse and polysedation harms.⁶ Dependence phenotypes include tolerance, dose escalation for anxiolysis/sedation or potentiation, and withdrawal syndromes (insomnia, anxiety, diaphoresis, autonomic symptoms) reported in case‑based literature; robust incidence remains unknown.⁵–⁷

Prescription stimulants (amphetamine products, methylphenidate) increase synaptic dopamine/norepinephrine via transporter blockade and/or presynaptic release, activating mesolimbic reinforcement pathways that can support misuse and stimulant use disorder in susceptible individuals.¹⁹,²² NSDUH 2023 estimates 3.9 million people aged ≥12 became addicted or misused prescription stimulants alone in the past year.¹⁹ A recent U.S. adult analysis reported that among adults using prescription stimulants, misuse occurred frequently and a clinically defined prescription stimulant use disorder occurred in a smaller but consequential subset; most affected individuals used their own prescriptions rather than diverted supply, consistent with iatrogenic trajectories.²² Withdrawal can include dysphoria, hypersomnia, fatigue, and anhedonia, which can entrench compensatory redosing and complicate interruption attempts.²²,²³ For pain clinics, stimulants matter most as comorbidity amplifiers (sleep disruption, anxiety, appetite effects) rather than as analgesics; prevalence for stimulant‑linked iatrogenic dependence specifically in pain cohorts remains unknown.¹⁹,²²

Antidepressants used for pain (SSRIs/SNRIs; eg, paroxetine, venlafaxine, duloxetine) inhibit serotonin reuptake (± norepinephrine reuptake) and can produce discontinuation syndromes through neuroadaptation despite minimal classic intoxication‑reinforcement.⁸,⁹ A 2024 meta‑analysis estimated discontinuation symptoms after antidepressant cessation at materially higher rates than placebo cessation and quantified severe symptoms in a minority, establishing that discontinuation can reach high clinical severity even when addiction frameworks do not apply.⁸ Pharmacovigilance work in global databases identifies disproportionate withdrawal signals for short half‑life and dual‑reuptake agents (eg, paroxetine, venlafaxine, desvenlafaxine, duloxetine), supporting a drug‑specific risk gradient.⁹ Discontinuation often includes dizziness, sensory disturbances (“electric shock” sensations), insomnia, irritability, and emotional lability; diagnostic mirroring (symptoms misread as relapse) drives re‑initiation.⁸,⁹ Trials that evaluate antidepressants for depression do not directly estimate discontinuation incidence in neuropathic pain populations; pain‑specific prevalence therefore remains unknown.⁸

Dopamine agonists (eg, pramipexole, ropinirole), used primarily for Parkinson disease and restless legs syndrome, directly stimulate dopamine receptors (often with D3 affinity) and can induce impulse control disorders that resemble behavioral addictions.¹⁰,²¹ FAERS signal detection work found strong associations between dopamine agonists and pathological gambling, hypersexuality, compulsive shopping, and related behaviors, with risk concentration in D3‑preferring agonists.¹⁰ A critical review reports wide prevalence ranges across cohorts and emphasizes patient‑level risk factors and dose effects; these behaviors often resolve or improve with dose reduction or discontinuation, supporting pharmacologic causation.²¹ Pain relevance arises through restless legs syndrome comorbidity, augmentation management, and dopaminergic exposure during chronic symptom care; prevalence within pain clinics remains unknown.¹⁰,²¹

Corticosteroids (eg, prednisone) activate glucocorticoid receptors and suppress inflammation but can suppress the HPA axis with prolonged systemic exposure, generating physiologic dependence that necessitates tapering to prevent adrenal insufficiency.¹¹ The major endocrine guideline states that short systemic courses (<3–4 weeks) generally do not require taper, whereas longer exposure increases suppression risk and requires a structured taper strategy and patient education.¹¹ Patients can experience glucocorticoid withdrawal syndrome during taper, with symptoms that overlap adrenal insufficiency and inflammatory disease flare, producing diagnostic mirroring that drives reinstatement.¹¹ Corticosteroids also produce mood and sleep effects, including euphoria/hypomania in short‑term use and depressive syndromes during longer exposure, which can contribute to psychological reliance.¹² Incidence of dependence syndromes in pain populations remains unknown because surveillance tracks prescriptions and adverse events rather than withdrawal physiology.¹¹,¹²

Carisoprodol (muscle relaxant) produces CNS depressant effects and metabolizes to meprobamate, a compound with established abuse liability; repeated exposure can generate sedative‑hypnotic–like dependence.¹³ DEA placed carisoprodol in Schedule IV, reflecting recognized abuse and dependence risk in the U.S. regulatory framework.¹⁴ Withdrawal after high‑dose or prolonged use can include insomnia, vomiting, tremor, anxiety, ataxia, hallucinations, and delirium, with severe cases requiring medically supervised discontinuation.¹³ Prevalence of iatrogenic dependence in pain clinics remains unknown; case‑based literature and regulatory scheduling establish risk plausibility rather than incidence.¹³,¹⁴

Butalbital combination analgesics (barbiturate‑containing headache products) potentiate GABAergic neurotransmission and carry barbiturate dependence risk plus a pain‑specific feedback loop: medication‑overuse headache.¹⁵,¹⁶ Reviews and position arguments emphasize tolerance, dependence, withdrawal risk, and drug‑induced headache syndromes as predictable outcomes with repeated use, supporting strict limitation and monitoring.¹⁵,¹⁶ Withdrawal can be severe and resembles other sedative‑hypnotic withdrawals; clinicians often require supervised detoxification protocols in entrenched use.¹⁵,¹⁶ Population prevalence remains unknown; public surveillance does not track butalbital misuse in a dedicated category.¹⁹

Ketamine (NMDA receptor antagonist) provides analgesia in selected refractory neuropathic pain contexts but carries dissociative intoxication potential and documented abuse liability.¹⁷,¹⁸ Reviews emphasize careful monitoring for psychiatric effects, cognitive symptoms, urinary tract injury signals in heavy use contexts, and patterns consistent with misuse/diversion.¹⁷,¹⁸ Dependence phenotypes in clinical pain protocols remain incompletely quantified because many harms derive from recreational high‑dose patterns; extrapolation to therapeutic dosing therefore requires caution.¹⁷,¹⁸ Incidence of ketamine use disorder arising from pain treatment remains unknown.¹⁷

OTC antihistamines and antitussives (diphenhydramine, dextromethorphan) contribute to pain‑adjacent iatrogenesis through self‑treatment of insomnia/anxiety and dissociative “escape” patterns, especially when clinicians fail to elicit OTC histories.¹⁸–²⁰ A systematic review supports diphenhydramine addiction potential based on accumulated case reports/series and detoxification experiences; dependence can sustain chronic high‑dose sedative use.¹⁸ Dextromethorphan can produce dissociative effects at high doses; case‑anchored literature describes compulsive continuation and functional collapse consistent with substance use disorder phenotypes in extreme use.¹⁹,²⁰ Prevalence remains unknown because NSDUH tracks “illicit” drug categories but does not isolate OTC anticholinergic or antitussive dependence as a standard category.¹⁹

Table sources: ASAM benzodiazepine tapering guideline²; EudraVigilance Z‑drug post‑marketing analysis²⁰; gabapentin misuse systematic review⁵ and FDA respiratory warning⁶; NSDUH misuse surveillance¹⁹; antidepressant discontinuation meta‑analysis⁸ and WHO withdrawal signal work⁹; FAERS dopamine agonist impulse control signal¹⁰ and review²¹; endocrine glucocorticoid taper guideline¹¹ and psychiatric adverse‑effect review¹²; carisoprodol review¹³ and DEA scheduling¹⁴; butalbital dependence/overuse literature¹⁵,¹⁶; ketamine abuse‑liability reviews¹⁷,¹⁸; diphenhydramine review¹⁸ and OTC misuse synthesis¹⁹,²⁰.

Clinical implications and mitigation

Clinicians should treat iatrogenic dependence as a predictable pharmacologic outcome in defined exposure patterns rather than as a patient moral failure.²,⁵,⁸

They must seek non-addictive alternatives and be sure they are understand the root cause of general, non-descript and hard-to-diagnose chronic pain in our youth. Prescribing physicians must be required to keep an auditable lowest-effective dose and tapering journal per child. We will discuss necessary policy and practice changes in detail in our next article.

It’s not up to the child and the parents to monitor for signs of overuse and addiction. Natural and integrative pain management therapies exist will be explored in detail soon. For benzodiazepines and Z‑drugs, clinicians should time‑box initial prescribing, document stop‑plans, avoid abrupt discontinuation in dependent patients, and implement structured tapers with symptom‑guided pacing to prevent seizure‑risk withdrawal and diagnostic mirroring–driven reinstatement.²,⁴ For gabapentinoids, clinicians should screen forand inform on risks of polysedation (concurrent sedatives, alcohol, opioids), counsel on respiratory depression risk, and monitor dose escalation and early refills, given FDA‑recognized harm signals and cohort‑heterogeneous misuse risk.⁵,⁶ For SSRIs/SNRIs used in pain, clinicians should distinguish discontinuation syndromes from relapse, implement gradual tapers (especially for short half‑life agents), and explicitly counsel that withdrawal symptoms can mimic the original symptom domain.⁸,⁹ For dopamine agonists, clinicians should counsel before initiation and repeatedly screen for new impulsive behaviors; clinicians should treat emergent ICDs as medication adverse effects and adjust therapy promptly.¹⁰,²¹ For systemic corticosteroids, clinicians should follow endocrine guidance on taper necessity by duration and dose context, educate patients about withdrawal vs adrenal insufficiency vs disease flare, and avoid abrupt cessation after suppressive exposure.¹¹ For butalbital and carisoprodol, clinicians should avoid long‑term use, monitor for dependence patterns, and plan supervised discontinuation when entrenched use exists.¹³–¹⁶ For ketamine protocols, clinicians should implement monitoring that explicitly includes misuse/diversion risk and psychiatric adverse effects, and clinicians should document dose ceilings and treatment endpoints.¹⁷,¹⁸ Routine medication reconciliation should include OTC sedatives and cough/cold agents because unrecognized OTC dependence can sabotage insomnia/anxiety and pain treatment plans.¹⁸–²⁰

Timeline sources: DEA scheduling of carisoprodol¹⁴; FDA boxed warning for Z‑drugs⁴; FDA gabapentinoid respiratory depression warning⁶.

The evidence underscores a need for policy shifts at HHS and beyond: enhanced surveillance to track iatrogenic dependence (not just misuse), mandatory patient education on withdrawal risks, and incentives for non-pharmacologic pain strategies like integrative mental health approaches (as you tease in future reports). This isn’t about demonizing doctors—many prescriptions start with good intent—but about acknowledging that long-term use can create entrapment cycles, especially when withdrawal mimics the original condition.

If the cartel crackdown is a win against external threats, tackling over-prescription and turned blind eyes to overuse and misuse could prevent millions of internal casualties from legal drugs and their role as gateways to street drugs.

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