Crit Care Shock (2019) 22:197-203

Carisoprodol intoxication: a comprehensive review Zulkifli Amin, Steven Zulkifly, Stephen Diah Iskandar

Abstract only a few case reports about carisoprodol in- Carisoprodol has been widely used as a muscle toxication and no guideline has been published. relaxant agent. In Indonesia, carisoprodol is This article aims to provide an overview about well-known as carnophene/zenith. Many re- carisoprodol intoxication, starting from the tailers sell this drug illegally, especially to sex mechanism of action to its management. In the workers to make them feel more relaxed. Due to body, carisoprodol is metabolized to meproba- high incidence of carisoprodol abuse, Drug mate by CYP2C19 enzyme. Diagnosis of Enforcement Administration (DEA) categorized carisoprodol intoxication is challenging because it into Schedule IV. Knowledge about pharma- carisoprodol and have opposite cokinetic and pharmacodynamic of carisopro- effect. Gastric lavage, administration of flu- dol are essential to be understood for proper mazenil and may be effective for diagnosis and management. Until now, there are acute intoxication case. . Key words: Carisoprodol, meprobamate, intoxication.

Introduction 160 mg and 32 mg . Based on Carisoprodol (N-isopropyl-2-methyl-2-propyl-1,3- Indonesia’s Drug Specialite Information (DSI/ propanediol dicarbamate, N isopropyl meproba- ISO), carnophene is indicated to relieve low back mate) was developed by Dr. Frank M. Berger as a pain, muscle spasm, tension type , dys- agent. Carisoprodol was syn- mennorhea, and chronic arthritis. (4) In Sulawesi, thesized to create a better muscle relaxing carnophene is widely used by sex worker to make property, safer, and less abuse potential than me- them feel less ashamed, more relaxed and probamate. (1) Decades after carisoprodol inven- confident to face their customer. (5) tion, several researches reported that carisoprodol The incidence of carisoprodol abuse have been was converted to meprobamate in human body by reported worldwide, therefore Drug Enforcement liver. (2,3) Administration (DEA) classified carisoprodol in In Indonesia, carisoprodol is known as carnophene Schedule IV list as a drug can lead to physical and (zenith), which contained 200 mg carisoprodol, p s yschological dependance. (6) In Norway, cariso- . prodol is one of the most abused drugs and causes fatality. (7-9) In Indonesia, many retailers sell carisoprodol illegally with average cost of cariso- From Division of Respirology and Critical Illness, Department prodol is IDR 40,000 - 100,000 (US$3 - US$7.5) of Internal Medicine, Faculty of Medicine Universitas for 10 pills. Many cases of carisoprodol intoxi- Indonesia, Cipto Mangunkusumo National General Hospital, cation are found in Indonesia, but not recorded Jakarta, Indonesia (Zulkifli Amin, Steven Zulkifly, Stephen properly. (4,5) Diah Iskandar). Knowledge about pharmacokinetic and pharma- codynamic of carisoprodol are essential for proper Address for correspondence: diagnosis and treatment. Until now, there is no Zulkifli Amin Division of Respirology and Critical Illness, Department of guideline about carisoprodol intoxication have Internal Medicine, Faculty of Medicine Universitas Indonesia, been published, only several case reports discuss Cipto Mangunkusumo National General Hospital, Jakarta, about this issue. The current review was conducted Indonesia to explore studies about carisoprodol intoxication Jalan Salemba Raya No. 6, Central Jakarta, Jakarta 10430 Email: [email protected] and its management.

Crit Care Shock 2019 Vol. 22 No. 4 197 Pharmacokinetic of carisoprodol than 1% is excreted unchanged and 4.7% excreted Absorption as meprobamate over 24 hours after administration Two studies tried to determine pharmacokinetic of 350 mg carisoprodol tablet. (18) properties of carisoprodol, using liquid chromatog- raphy-mass spectrometry (LC-MS) method. Simon Mechanism of carisoprodol intoxication et al measured plasma level of carisoprodol and After carisoprodol is metabolized by enzyme meprobamate over 48 hours after administration of CYP2C19 in liver, it undergoes biotransformation 250 and 350 mg carisoprodol, while the study con- to three metabolic products, such as hydroxy cari- ducted by Bramness et al measured plasma level of soprodol, hydroxy meprobamate, and meproba- carisoprodol and meprobamate for 11 hours and 45 mate. In human, the main metabolic product is me- minutes after administration of 700 mg cari- probamate. Meprobamate acts similar with benzo- soprodol. (10,11) The comparison of pharmacoki- diazepine and by modulating the func- netics properties is given in Table 1. Another tion of γ aminobutyric acid A (GABAA) receptor. study found that rapid gastrointestinal absorption (19) GABAA receptor is an ionotropic receptor of carisoprodol resulted in peak plasma concentra- that directly connected with Cl-channel, thus the tion of 4-7 mg/l, which were achieved within 2-4 activation of this receptor causes the increase of hours and onset of action within 30 minutes after chloride ion conductance and hyperpolarization of ingestion. (12) Carisoprodol has a pKa of 4.2, post-synaptic cells. (20) The impact of hyperpolar- which facilitate it to be highly absorbed in stomach ization of the cells is inhibition of intraneuronal and small intestine. (13) transmission of descending reticular formation and spinal cord, which explained the -hypnosis Distribution effect of carisoprodol. (21) Among other receptors, Carisoprodol is rapidly distributed to central nerv- GABAA receptors are the major fast synaptic inhi- ous system. Protein binding of carisoprodol and bition receptor in central nervous system. (20) meprobamate are approximately 60% and 25%, Meanwhile, four cases of carisoprodol intoxication respectively. (13) There is no report of volume of showed similar manifestations to serotonin syn- distribution (Vd) for carisoprodol in human until drome, including hypertension, tachycardia, now. Based on animal study by US National Toxi- choreiform movements, shivering and tremor. (22) cology program, estimated Vd of carisoprodol is These findings showed that carisoprodol had dif- 0.72 l/kg in rats and 0.65 l/kg in mice. An analysis ferent mechanisms beside interaction with using two-compartment pharmacokinetic model GABAA receptor. It hypothesized that cari- described that estimated Vd for carisoprodol in soprodol had direct effect to central nervous sys- human is 0.93-1.3 l/kg, while for meprobamate is tem without conversion to meprobamate. However, 1.4-1.6 l/kg. (14) the mechanism of this effect was still unclear. GABAA receptors are the major fast synaptic inhi- Metabolism bition receptor in central nervous system. GABAA Carisoprodol is metabolized in liver by enzyme receptor is member of cys loop ligand gated ion CYP2C19, produces its primary metabolite, me- channels, including six α subunits, three β subu- probamate. Carisoprodol is also metabolized to nits, three γ subunits, three ρ subunits, as well as hydroxy carisoprodol in much lesser extent by un- one ϵ, δ, θ, and π subunit. (20) known enzyme. Both meprobamate and hydroxy Many studies tried to solve the question why cari- carisoprodol are metabolized to hydroxy mepro- soprodol had different effect than its metabolite, bamate, then partially conjugated. (15) The rela- meprobamate. Gonzales et al found that cari- tionship between variation in CYP2C19 activity soprodol directly activate human α1β2γ2 GABAA and metabolism of carisoprodol has been proven to receptor. However, this potentiation of GABA- be correlated with mephenytoin hydroxylation pol- gated currents was only occurred at micromolar ymorphism (using probe drug S-mephenytoin). (3) concentration. On the contrary, high concentration Many drugs may interact with CYP2C19 and in- of carisoprodol (millimole concentration) produced hibit the metabolism of carisoprodol. , GABA inhibition, followed by rebound currents , omeprazole, and oral contraceptive after termination of the drug. (23) This phenome- drugs have been shown to reduce the metabolism non could be explained by dose-dependent channel of S-mephenytoin. (11,15-17) block of GABAA receptor that limits the maxi- mum total current conducted, as found in other study with barbiturate compounds. (24,25) Even, Carisoprodol is primarily excreted in urine. Less in the absence of GABA neurotransmitter, micro- . .

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molar concentration of carisoprodol causes rapid festations will be initiated with acute carisoprodol and reversible inward currents that can be blocked intoxication syndrome then followed by meproba- by picrotoxin, a non-competitive channel blocker mate intoxication. However, none of the case re- for GABAA receptor. These inward currents are ported these clinical manifestations. (19,29) significantly higher than inward currents produced Acute carisoprodol intoxication causes decreases by meprobamate. (23) level of consciousness to or semi-coma. This Study in multiple combination of GABAA recep- high concentration of carisoprodol in serum (>25 tors found that meprobamate also had direct-gating µg/ml) also causes sign and symptoms of serotonin and allosteric effect in α1-6β2γ2 GABAA receptor, and syndrome that overlap each with the largest effect in combination of α5 subu- other. The clinical manifestations including nys- nit. (26) However, carisoprodol is more potent and tagmus, pupil dilatation, decreased light reflex, efficacious than its metabolite. Administration of diplopia, hyperthermia, tachycardia, elevated blood therapeutic dosage is enough to activate GABAA pressure, agitation, , elevated muscle tone, receptor. (20) hyper reflex, and involuntary movement (myo- In behavioral approach, carisoprodol has barbitu- clonic jerk, choreiform, and myoclonic encephalo- rate-like effects, not solely due to its metabolite, pathy). (19,29) meprobamate. Carisoprodol effect of locomotor Carisoprodol intoxication is easily occurred in pa- activity depression lasting from 40 minutes to 2 tients with absence or decreased activity of hours in mice. The offset of motoric/behavior de- CYP2C19, thus carisoprodol is metabolized slowly pression is parallel with the falling plasma concen- and the concentration of carisoprodol in serum is tration of carisoprodol. (23,27) This phenomenon elevated to 4 times higher than normal people. This proves that effects of carisoprodol are rare condition is found in 3-5% of Caucasian and not fully caused by meprobamate, considering the African, and 15-20% of Asian. Omeprazole and plasma half-life of meprobamate is 8 times longer. fluvoxamine, a CYP2C19 inhibitor, can increase (19) Another study also found that inhibition of the carisoprodol concentration and decrease me- hepatic enzyme that decreased metabolism of cari- probamate concentration. Contrary, CYP2C19 in- soprodol caused longer duration of carisoprodol- ducers, such as and rifampin, decrease the induced paralysis. (28) carisoprodol concentration and increase meproba- Another proof is drug discriminative study. Com- mate concentration. (30) pounds like , , and Prolonged agitation and seizure due to carisoprodol meprobamate can fully substitute for the discrimi- intoxication cause myoglobinuria and resulting in native stimulus effects of carisoprodol. The effects renal failure. A case report found agitation and of carisoprodol are fully blocked by bemegride, a muscle rigidity in patient, who consumed 35 grams barbiturate antagonist, but not an- of carisoprodol, lasting for 48 hours. Even after got tagonist. Meanwhile, , a benzodiazepine treatment in hospital for 48 hours, the concentra- antagonist but not barbiturate antagonist, fails to tion of carisoprodol in serum was still categorized produce dose-dependent blockade for carisoprodol. as toxic concentration (71 µg/ml). (31) (23) Meprobamate intoxication is defined as serum Although carisoprodol has the same effect as bar- concentration above 60 µg/ml, which manifests in biturate, carisoprodol is not acting at the barbitu- central nervous system depression, similar effect to rate site receptor. Homomeric ρ1 GABA receptors barbiturate. Sign and symptoms in meprobamate and α1 receptors are sensitive to cari- intoxication including coma or semi-coma, respira- soprodol, but insensitive to barbiturate. Moreover, tory depression, hypotension, muscle flaccid, and W328M mutation at ρ1 GABA receptors confer diminished physiology reflex. (32) The difference sensitivity to barbiturate, but not carisoprodol. (23) manifestations of carisoprodol and meprobamate intoxication were firstly realized when a child Clinical manifestation of carisoprodol intoxica- showed agitation after consuming 1200 mg of cari- tion soprodol. (33) The effect of carisoprodol and me- The symptoms of carisoprodol intoxication are probamate may be worsened if the patient also simply classified into two different syndromes, consumes , benzodiazepine, , or tri- depend on which substance is dominant, either cyclic antidepressants. (34) carisoprodol or meprobamate. The clinical mani- festations of each syndrome will be elaborated fur- Laboratory diagnosis of carisoprodol intoxica- ther in below. The half time of carisoprodol is 1- tion 1.5 hours and meprobamate is 8 times longer, The methods to determine plasma carisoprodol and around 10 hours. Theoretically, the clinical mani- meprobamate level keep developing. Carisoprodol . and Crit Care Shock 2019 Vol. 22 No. 4 199 and meprobamate are aliphatic compound without onist agents, but the studies did not show promis- any significant ultraviolet absorbance or fluores- ing results. In 1981, flumazenil (1,4- cence. It is primarily measured by gas chromatog- imidazodiazepines) was introduced and showed raphy (GC) or gas chromatography-mass spec- significant outcome as a potent benzodiazepine trometry (GC-MS). 35,36) These methods have antagonist. (42,43) As mentioned above, cari- limitations because carisoprodol and meprobamate soprodol shows similar effect to benzodiazepine, are labile in heat. This problem can be overcome which acts specifically at GABA receptor. Chlo- by hydrolyzed compounds with potassium hydrox- ride ions are found abundantly in extracellular with ide (KOH), and the hydrolysates are trimethylsi- sodium ion. When bind to GABA lylated before GC-MS analysis. However, this receptors, GABAs are released from pre-synaptic method is time consuming and may cause delayed site and open chloride channel in post-synaptic treatment. (37) The other solution is using liquid site, resulting in the influx of chloride ion into the chromatography-mass spectrometry (LC-MS) nerve cell and cause hyperpolarization. (42) equipped with electrospray ionization (ESI). (38) Flumazenil acts as weak agonist and strong com- The newest method to determine carisoprodol and petitive antagonist to benzodiazepine receptors in its metabolite meprobamate is liquid chromatog- central nervous system. (42) Flumazenil has mini- raphy with tandem mass spectral detection (LC- mal effect on relaxing muscle. The main effect is MS) using oral fluid sample. In the future, this strong competitive antagonist to GABA receptor in method can be used for therapeutic drug monitor- central nervous system, but not in peripheral nerv- ing, detection of driving under the influence of ous system, causing inhibition of benzodiazepines carisoprodol, pain management, and overdose de- effects. (44) tection. (39) Therapeutic serum level of cari- The lipophilic characteristic of flumazenil makes it soprodol ranging from 5-20 µg/ml. If serum level rapidly enough to penetrate the central nervous increases to 30-100 µg/ml, stupor and lethargy are system. However, the oral bioavailability after first manifested. Serum level is correlate with clinical pass metabolism and hepatic clearance is only effects. (40) 16%, so intravenous administration is the route of Postmortem analysis using GC-MS showed that choice. Elimination half-life of drug is short, rang- distribution of meprobamate and carisoprodol in ing from 0.7-1.3 hours. However, flumazenil has a peripheral blood, central blood, and liver were dif- large volume of distribution (0.63-10.06 l/kg). ferent. If blood specimen is absence or contaminat- Flumazenil is excreted by urine, after undergoes ed, liver specimen may be used to approximate complete hydroxylation by hepatic microsomal plasma concentration of meprobamate or cari- oxidative to inactive state and bound to glucu- soprodol. (41) ronide. (43) One of the clinical indications of flumazenil is the Acute management of carisoprodol intoxication management of benzodiazepine overdose. Several Until now, there is no published guideline for studies have shown that flumazenil intravenous management of carisoprodol intoxication. A case administration alone could improve the conscious- report recommends gastric lavage soon after inges- ness in patients with benzodiazepine intoxication tion. Administration of activated charcoal can be within minutes. The effect of flumazenil lasting given 1-2 hours after ingestion. Intubation and me- from 1-5 hours. (43,44) Low dose flumazenil have chanical ventilation is considered if indicated. In- been reviewed as therapy for benzodiazepine de- travenous fluid should be given to produce good pendence. (45) urine flow and prevent deterioration. Urine Recent study found that flumazenil was partially output should be monitored and targeted to 0.5-1 inhibit the carisoprodol effects. However, be- ml/kg/hour. (40) megride was reported can act as fully antagonist to Roberge et al prescribed flumazenil 0.2 mg intra- carisoprodol and meprobamate effects. (19) Be- venous bolus over 2 minutes in patient with acute megride (β-ethyl-β-methylglutarimide) was firstly intoxication carisoprodol with Glassgow Coma introduced in 1954 and have been widely used for Score (GCS) 9. After administration, the patient barbiturate poisoning since 1957, with variable become more alert within 2 minutes but still mildly success. (46) In animal study, administration of 5- somnolent. Five minutes later, second administra- 10 mg/kg of body weight bemegride antagonized tion of flumazenil, with the same dose, reversed all the pentobarbital effect (barbiturate) but not the sign of intoxication within 2 minutes. (40) chlordiazepoxide (benzodiazepine). (47) In human Naloxone, methylxanthines, and cholinergic agents study, administration of 50 mg bemegride intrave- were firstly investigated for benzodiazepine antag- nously was used to reverse the sedation effect of . .

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0.5 gram of thiopentone, a short acting barbiturate Conclusion drug. (48) Carisoprodol is rapidly absorbed in gastrointestinal tract and its effects occur 30 minutes after inges- Discussion tion. Carisoprodol is metabolized by CYP2C19 in The initial management of carisoprodol intoxi- liver to meprobamate. Both carisoprodol and me- cation is prompt diagnosis following by appropri- probamate are central nervous system depressant ate treatment, to reduce the morbidity and mortal- by binding to GABAA receptor. Although mepro- ity rate. In developing countries, intoxication diag- bamate is carisoprodol metabolite, the clinical nosis was still challenging due to limited resources manifestations of intoxication are opposite to each of laboratory examination in health facilities. His- other. Several studies reported that carisoprodol tory of intoxication and clinical manifestation that had benzodiazepine-like effect and others reported suspicious to intoxication symptomps, could be- barbiturate-like effect. Supportive management come strong predictors. The epidemiology of drug (intravenous fluid, gastric lavage and activated abuse in local area could help clinicians to diag- charcoal) have been done in several cases and nose the intoxication. showed satisfying results. The use of flumazenil Drug abuse has been a serious concern due to af- (benzodiazepine antagonist) or bemegride (barbitu- fecting the physical and socio-economic well being rate antagonist) as carisoprodol antidote may be of the country. The incidence of drug abuse in In- considered to treat carisoprodol intoxication. donesia was particularly high, however, the report of carisoprodol abuse was limited in several prov- Conflict of interests ince. Public policies relating to drug abuse preven- The authors declare that there is no conflict of in- tion and demand reduction should be made by terest regarding the publication of this article. government.

Table 1. Pharmacokinetic properties of carisoprodol and its metabolite, meprobamate, after administration of 250 mg, 350 mg, and 700 mg carisoprodol (10,11)

Properties Simon, et al Bramness, et al 250 mg carisoprodol 350 mg carisoprodol 700 mg carisoprodol Carisoprodol Meprobamate Carisoprodol Meprobamate Carisoprodol Meprobamate Cmax 1.24 1.84 1.78 2.46 3.7 4.1 (µg/ml) Tmax 90 216 102 270 83 270 (min) T1/2 104.4 580.2 117.6 577.8 96 NA (min) AUC 4.51 32.33 7.00 45.98 11.3 26.5 (µg/ml/h)

Legend: Cmax=maximum concentration; Tmax=transport maximum; T1/2=the half life of drug; AUC=area under the curve.

Crit Care Shock 2019 Vol. 22 No. 4 201 References

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