Substance Use Disorder of Nitrous Oxide Uncommon in Sickle Cell Disease


Results from the PHEDRE study show nitrous oxide in a gas mixture for pain was not problematic for most patients with sickle cell disease in France.

Professor Caroline Victorri-Vigneau | Image Credit: Sphere Inserm

Professor Caroline Victorri-Vigneau

Credit: Sphere Inserm

An equimolar oxygen-nitrous oxide mixture (EMONO), often used for short-term analgesia, was not associated with substance use disorder (SUD) in the majority of patients with sickle cell disease (SCD) from a recent study in France.1

Results from the PHEDRE study showed approximately 40% of patients with SCD were treated with EMONO, of which only 11% had SUD characterized by two positive criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) in most cases.

“Our results showed that the use of EMONO was not problematic for the majority of patents, which should prompt a change in the modalities of pain management and the reinforcement of psychological care,” wrote the investigative team, led by Professor Caroline Victorri-Vigneau, clinical pharmacology service, CHU Nantes.

Nitrous oxide in a gas mixture is commonly used in medical practices due to its analgesic and anxiolytic properties.2 Hospitalizations for vaso-occlusive crises (VOCs) use EMONO for the rapid management of pain—those with SCD may represent a high-risk population for substance misuse given the significant pain crises faced by the patients.1

Poor pain management can expose patients to the risk of pseudoaddiction, defined as a constant fear of pain, and occurs when a patient attempts to obtain a higher analgesic dose to relieve pain. However, unlike SUDs, analgesic-seeking behavior halts after pain is effectively treated and relief has been achieved.3

Potential SUDs with EMONO are an issue for patient treatment strategies in SCD, requiring specific evaluation, but few data exist on the concern. The PHEDRE study sought to evaluate the use of EMONO in a population of French patients with SCD.

The study population was recruited after attending routine follow-up in a reference center between September 2015 and December 2017. A physician completed a form on the patient’s demographic and clinical data and hospitalizations for VOCs in the past 12 months. A standardized questionnaire by phone interview included the number of at-home analgesics and use of psychoactive medications in the past 12 months, and the effects sought and experienced with EMONO.

Investigators assessed SUD using DSM-5 criteria, defined by whether EMONO was used for analgesic effects within or outside a painful context. Based on the DSM-5, SUD was defined by meeting 2 or more of the 11 criteria for a mild condition and by ≥6 for a severe condition.

Approximately 2000 people were estimated to be eligible for the study in France. Ultimately, 993 patients were included in the analysis and 339 patients (39%) had used EMONO the 12 months before the study. Most (86%) had been hospitalized ≥1 time for VOC in the past 12 months, with more frequent SUD for analgesics other than EMONO (64%).

Nearly all patients (99.7%) sought an analgesic effect with EMONO, but 68% of patients were seeking other effects, including 38% seeking “therapeutic effects only” and 53% looking for a “gliding” effect. Upon analysis, only 38 (11%) of the 335 consumers had a SUD for EMONO, with 33 (9.9%) meeting the criteria for a mild SUD, according to the DSM-5.

A comparison was performed between patients with ≥1 SUD criterion (27%) for EMONO and patients with no criteria (63%). The most prevalent SUD criteria were persistent usage despite persistent or recurrent social or interpersonal problems (15.3%) and using more substance than planned or for a longer interval than desired (14.8%).

Independent risk factors associated with ≥1 SUD criterion were the feeling of effects aside from the expected therapeutic effects of EMONO, ≥1 hospitalization for VOC in the past 12 months, and a SUD for ≥1 analgesic drug.

Victorri-Vigneau and colleagues noted a better understanding of the concepts of addiction and pseudoaddiction would be beneficial in the case of repeated requests for analgesics. These results suggest the main EMONO motivation in PHEDRE appeared to be the analgesic effect, rather than the euphoric effects.

“The memory of previous administrations and the instantaneous effect of EMONO with immediate pain relief, compared to other analgesic therapies with a longer delay of action, could explain the positive effects felt and sought by patients,” they wrote.


  1. Gérardin M, Rousselet M, Couec ML, et al. Substance use disorder of equimolar oxygen-nitrous oxide mixture in French sickle-cell patients: results of the PHEDRE study. Orphanet J Rare Dis. 2024;19(1):124. Published 2024 Mar 18. doi:10.1186/s13023-024-03133-w
  2. Fidalgo M, Prud’homme T, Allio A, Bronnec M, Bulteau S, Jolliet P, et al. Nitrous oxide: What do we know about its use disorder potential? Results of the French Monitoring Centre for Addiction network survey and literature review. Subst Abuse. 2019;40(1):33–42.
  3. Dydyk AM, Sizemore DC, Haddad LM, Lindsay L, Porter BR. NP Safe Prescribing Of Controlled Substances While Avoiding Drug Diversion. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022
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