Utility of Dantrolene in Treating Neuroleptic Malignant Syndrome

Dantrolene medication vial and syringe on abstract medical background

Take Home Points

  • Neuroleptic malignant syndrome (NMS) is a diagnosis of exclusion, typified by altered mental status, hyperthermia, and muscle rigidity several days after antipsychotic initiation or dose escalation or withdrawal of dopaminergic agents.
  • Effective management is crucial as NMS is associated with a 30-day mortality rate of about 5%.
  • The mainstay of treatment includes discontinuation of the offending agent, aggressive temperature management, and liberal use of benzodiazepines.
  • Evidence is limited to case series and reports, but dantrolene may be considered in NMS with severe rigidity.
  • Call the Utah Poison Control Center at 1-800-222-1222 at any time, 24/7, for assistance managing known or suspected neuroleptic malignant syndrome.

Neuroleptic Malignant Syndrome1,2

The exact mechanism of Neuroleptic Malignant Syndrome (NMS) is not completely understood. Initial case reports of a syndrome causing extreme muscle rigidity and hyperthermia were first documented with the use of haloperidol. There are two general hypotheses regarding the pathogenesis of NMS. The first hypothesis is that repeated treatment with dopamine receptor blockers may cause inactivation of neuronal firing. This reduced firing has been linked to both the clinical efficacy of antipsychotics and extrapyramidal side effects and is thought to play a role in the development of NMS, although the relationship is not fully understood. Another hypothesis suggests that dopamine blockade in the hypothalamus impairs heat dissipation, while blockade in the caudate nucleus, putamen, and ventral striatum causes muscular rigidity. Autonomic symptoms are thought to result from sympathoadrenergic system hyperactivity.

Though the precise role of dopamine in the development of NMS is unclear, it is considered a key factor, as the medications implicated in NMS all have dopamine antagonist effects. NMS occurs most frequently with high-potency first-generation antipsychotics like haloperidol, fluphenazine, and pimozide. However, it has also been reported with second-generation antipsychotics, as well as with metoclopramide, droperidol, and tetrabenazine. Additional risk factors for NMS include dehydration, use of multiple antipsychotic medications, high or escalating doses of antipsychotics, parenteral drug administration, and a previous episode of NMS.

The diagnosis of NMS is dependent on patient history and presenting symptoms. According to the DSM-5 the following criteria must be met: exposure to a dopamine blocking drug and severe muscular rigidity, plus at least two of the following: diaphoresis, dysphagia, tremor, incontinence, altered level of consciousness, mutism, tachycardia, elevated or labile blood pressure, leukocytosis, and elevated serum creatinine. Based on case reports and case series, patients often present with dysautonomia, high-grade hyperthermia, altered mental status, and increased muscle tone. Symptom onset is typically gradual, starting within one week of antipsychotic initiation or dose increase in 66% of cases and within 30 days in nearly all cases. 

NMS is a diagnosis of exclusion, and it is critical to rule out other causes of hyperthermia and rigidity, such as malignant hyperthermia, heat stroke, infection, and acute intoxication. NMS is often confused with conditions such as serotonin syndrome and lethal catatonia. In these cases, patient history, onset of symptoms, muscular findings, and mannerisms are key to differentiating the disorders. Mental status is generally depressed in NMS, though patients are delirious. Clonus and hyperreflexia are absent. Onset is slow, developing over days.

Despite treatment, mortality rates remain high. Historically, mortality rates from NMS have ranged from 20% to 30%. However, more recent reports suggest that 30-day mortality is closer to 4.7% and one-year mortality is 15.1%. 

Treatment of NMS includes discontinuing the offending agent and providing supportive care. However, discontinuing the agent may not always be possible with long-acting injectable antipsychotics, and may not be sufficient with severe symptoms. There are several proposed drug therapies for NMS, but none have proven definitive efficacy. Case reports have suggested that benzodiazepines may treat symptoms in mild NMS cases. Dopaminergic agents, such as bromocriptine, have also been used and shown to benefit patients by decreasing recovery time. Finally, dantrolene has been proposed as a possible treatment for NMS.

Dantrolene3

Dantrolene is a skeletal muscle relaxing agent. Dantrolene works by inhibiting ryanodine receptor type 1, preventing the binding of ryanodine and inhibiting the release of calcium from the sarcoplasmic reticulum. Dantrolene acts primarily on skeletal muscle receptors; thus, when activated, it results in lower levels of free calcium and decreased skeletal muscle contraction. The result is skeletal muscle weakness without paralysis.

Dantrolene is available as an intravenous solution (brand names Dantrium®, Revonto®, and Ryanodex®) and oral capsules. Dantrolene is indicated for the acute treatment and prevention of malignant hyperthermia during anesthesia. Due to its effectiveness in malignant hyperthermia, it has been proposed to be used for other disorders of acute hyperthermia, such as NMS, heat stroke, serotonin syndrome, monoamine oxidase inhibitor overdose, and thyroid storm. However, its efficacy for conditions other than malignant hyperthermia is limited, and it is not FDA-approved for these conditions.

Dantrolene Efficacy

Due to the relatively rare and heterogeneous nature of NMS, data on the efficacy of various agents is limited. To date, there are no prospective trials comparing the efficacy of dantrolene with either benzodiazepines or dopaminergic agents.

Dantrolene’s use in practice is limited to case reports and case series. Variable effects have been reported. Some case reports have demonstrated improvement with rigidity in patients treated with dantrolene,4,5 while others have shown variable improvement.4 However, given the significant heterogeneity of NMS, it is difficult to interpret case reports alone without larger prospective studies.

Several meta-analyses have been published compiling the available case reports and case series of patients with NMS. One large meta-analysis included 271 case reports of patients diagnosed with NMS.6 Cases were divided into four treatment groups: dantrolene alone, dantrolene plus other therapies (bromocriptine, amantadine, or electroconvulsive therapy (ECT)), other therapies alone, or supportive care. Outcomes assessed included effectiveness within 24 hours of initiating treatment, mortality, and complete time of remission of disease. Dantrolene monotherapy had the highest efficacy rate at 24 hours, at 76.7%. However, the complete time of remission with dantrolene was comparable to both other therapies alone and supportive therapy only. Additionally, dantrolene monotherapy was associated with higher rates of mortality as compared to other treatment groups. This review is limited by the fact that it did not differentiate groups based on baseline symptoms or severity of illness.

A second case series analysis sought to compare the effectiveness of NMS treatments, including a subgroup analysis based on disease severity.7 This analysis included 405 case reports of NMS. Overall, no statistical difference in mortality was found between patients treated with dantrolene and those treated with symptomatic therapy. However, in patients with severe disease, those treated with pharmacotherapy (either dantrolene or bromocriptine) had higher survival rates than those treated with symptomatic therapy alone. Again, the retrospective nature of this study and disease heterogeneity limit its conclusions.

When looking at both international and United States guidelines published on the treatment of NMS,8 seven of the fourteen guidelines recommend the use of dantrolene. Four of these guidelines do not specify when to use dantrolene but list it as a therapy option. The other three guidelines only recommend dantrolene use with severe symptoms. It is important to understand that dantrolene is only expected to help ameliorate muscle rigidity and cannot directly treat tachycardia, hypertension, hyperthermia, or delirium.

Dantrolene Safety

Adverse events related to IV dantrolene for NMS have not been thoroughly evaluated. A retrospective cohort study evaluated patient tolerability of oral dantrolene for myalgia, fatigue, and muscle cramps.9 The most common side effects experienced were headache and fatigue. Three of the 164 patients (1.8%) experienced elevated liver enzymes requiring discontinuation of therapy.

Commonly reported side effects of dantrolene in healthy patients were dizziness and dyspnea. There is concern that in patients with end-stage pulmonary disease, dantrolene administration may lead to respiratory failure.

Dantrolene should be avoided in patients receiving calcium channel blockers, as its administration in such patients has been linked to hyperkalemia and myocardial depression via an unclear mechanism.

If extravasation occurs, dantrolene can cause thrombophlebitis and tissue necrosis. Therefore, administration should always occur through a central line or a large peripheral vein. If extravasation occurs, the solution should be gently aspirated, and the affected extremity elevated.

Dantrolene Dosing

The most commonly accepted dosing regimen for dantrolene is 1-2.5 mg/kg as a single dose. If the patient shows rapid temperature reduction and decreased rigidity, it is recommended to continue dantrolene at 1 mg/kg every 6 hours. The maximum recommended dose of dantrolene is 10 mg/kg/day. The duration of dantrolene therapy is not well established. However, switching to oral dantrolene or taper dosing is generally recommended after the patient is stabilized or symptoms have resolved.

Administration time varies depending on the product brand. If Ryanodex® is administered, it should be given over 1 minute. If either Dantrium® or Revonoto® is administered, it should be administered over at least 1 hour.

Where Does Dantrolene Fit in Managing NMS?

As mentioned previously, there is no antidotal treatment for NMS, and care is supportive. Intravenous fluids are indicated to replace insensible losses with high metabolic demands. Liberal use of parenteral benzodiazepines will simultaneously treat rigidity, hyperthermia, tachycardia, and hypertension. Dopaminergic agonists such as bromocriptine may be useful but must be administered by mouth or via other enteral access.

Dantrolene may be useful in cases with significant muscle rigidity. If there is no clear improvement in rigidity after dantrolene administration, do not continue dantrolene.

Call the Utah Poison Control Center at 1-800-222-1222 at any time, 24/7, for assistance managing known or suspected neuroleptic malignant syndrome.

References

  1. Wijdicks EFM, Ropper AH. Neuroleptic Malignant Syndrome. Hardin CC, ed. N Engl J Med. 2024;391(12):1130-1138. doi:10.1056/NEJMra2404606
  2. Strawn JR, Keck PE, Caroff SN. Neuroleptic Malignant Syndrome. AJP. 2007;164(6):870-876. doi:10.1176/ajp.2007.164.6.870
  3. N. Juurlink D. Antipsychotics. In: Nelson LS, Howland MA, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS, eds. Goldfrank’s Toxicologic Emergencies, 11e. McGraw-Hill Education; 2019. Accessed May 27, 2025. accesspharmacy.mhmedical.com/content.aspx?aid=1163014148
  4. Ngo V, Guerrero A, Lanum D, et al. Emergent Treatment of Neuroleptic Malignant Syndrome Induced by Antipsychotic Monotherapy Using Dantrolene. Clin Pract Cases Emerg Med. 2019;3(1):16-23. doi:10.5811/cpcem.2018.11.39667
  5. Whyte CJ, Rosini JM. Dantrolene for Treatment of Suspected Neuroleptic Malignant Syndrome. Journal of Emergency Nursing. 2018;44(2):207-209. doi:10.1016/j.jen.2017.11.008
  6. Reulbach U, Dütsch C, Biermann T, et al. Managing an effective treatment for neuroleptic malignant syndrome. Crit Care. 2007;11(1):R4. doi:10.1186/cc5148
  7. Kuhlwilm L, Schönfeldt‐Lecuona C, Gahr M, Connemann BJ, Keller F, Sartorius A. The neuroleptic malignant syndrome—a systematic case series analysis focusing on therapy regimes and outcome. Acta Psychiatr Scand. 2020;142(3):233-241. doi:10.1111/acps.13215
  8. Schönfeldt-Lecuona C, Kuhlwilm L, Cronemeyer M, et al. Treatment of the Neuroleptic Malignant Syndrome in International Therapy Guidelines: A Comparative Analysis. Pharmacopsychiatry. 2020;53(02):51-59. doi:10.1055/a-1046-1044
  9. Ibarra Moreno CA, Kraeva N, Zvaritch E, Jungbluth H, Voermans NC, Riazi S. Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia–Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability. Anesthesia & Analgesia. 2023;136(3):569-577. doi:10.1213/ANE.0000000000006207

Author: Rachel Dietz, PharmD, PGY2 Emergency Medicine Pharmacist Resident, Intermountain Medical Center

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