Evaluating the safety and efficacy of dextromethorphan/quinidine in the treatment of pseudobulbar affect

Figures & data

Table 1 Summary of previous treatment studies in pseudobulbar affect and pathological laughing and crying

Publication	Patient population	Intervention and dose	Number of subjects	Outcome	Response
Case reports and case series
Komurasaki et al^Citation87	Stroke	Thyrotropin-releasing hormone	4	Number of episodes	2/4, decreased frequency
Mukand et al^Citation88	Stroke	Sertraline	2	PLACS^Citation21	Decreased frequency
Nahas et al^Citation89	Stroke, MS, TBI	Fluoxetine, Paroxetine, Sertraline	5	Self and clinician observation	5/5, decreased frequency
McCullagh and Feinstein^Citation90	ALS	Fluoxetine, Sertraline	3	Self and clinician observation	Crying responded, laughing did not
Ramasubbu^Citation91	Stroke	Lamotrigine	1	PLACS	Improved
Kim et al^Citation92	ICH; SAH	Mirtazapine	3	PLACS	Decreased frequency
Chahine and Chemali^Citation93	TBI	Lamotrigine	4	Self and clinician observation	4/4 completely stopped
Giacobbe and Flint^Citation94	Stroke	Citalopram	1	Self and clinician observation	Completely stopped
Ferentinos et al^Citation95	ALS	Duloxetine	1	CNS-LS^Citation96	Decreased severity
King and Reiss^Citation97	PML	Citalopram	1	Self and clinician observation	Decreased severity
Controlled trials
Schiffer et al^Citation22	MS	Amitriptyline	12	Episode log	Decreased frequency
Andersen et al^Citation20	Stroke	Citalopram	16	Self and clinician observation	Decreased frequency
Robinson et al^Citation21	Stroke	Nortriptyline	28	PLACS	Decreased severity

Abbreviations: ALS, amyotrophic lateral sclerosis; CNS-LS, Center for Neurologic Study-Lability Scale; ICH, intracerebral hemorrhage; MS, multiple sclerosis; PLACS, Pathological Laughing and Crying Scale; PML, progressive multifocal leukoencephalopathy; SAH, subarachnoid hemorrhage; TBI, traumatic brain injury.

Table 2 Summary of dextromethorphan and dextrorphan pharmacodynamics and plasma concentrations

Parameter	Dextromethorphan	Dextrorphan
Ki for NMDA receptor^Citation26,Citation28,Citation29	3,500 nM (950 ng/mL)	200 nM (52 ng/mL)
Kd sigma receptor^Citation26,Citation28,Citation29	57 nM (4 ng/mL)	400 nM (103 ng/mL)
Cssav with DM/Q^Citation52,a	104 ng/mL	97.3 ng/mL
Average concentrations CYP2D6 EMs (cough)b	2 ng/mL	NA
Average concentrations CYP2D6 PMs (cough)b	207 ng/mL	NA

Notes:

a Based on 30 mg dextromethorphan/10 mg quinidine bid for 7 days in EMs;

b Drugs and human performance fact sheet: dextromethorphan.⁹⁸

Abbreviations: bid, twice daily; Css_av, average concentration at steady-state; CYP2D6, cytochrome P450 2D6; DM, dextromethorphan; EM, extensive metabolizer; K_d, dissociation constant; K_i, inhibitory constant; NA, not available; NMDA, N-methyl-D-aspartate; PM, poor metabolizer; Q, quinidine.

Table 3 Dextromethorphan, dextrorphan, and quinidine human plasma concentrations reported in the literature

Dextromethorphan (DM), dextrorphan (DX), and quinidine (Q) plasma concentration (ng/mL)	Observation
Healthy subjects
DM =64–113	Mean/geometric mean Cmax with bid dosing of DM/Q 30/10 mg for 7 days^Citation52
Q =40
DM =115 (277)	Mean (maximum) Cmax with long-term dosing of DM/Q 30/30 mg
DM/Q in PBA clinical trials
DM =114±56.5	Mean ± SD on day 85 of DM/Q 30/30 mg bid (DM/DX =1.4)^Citation46
DX =82.2±31.5
Q =168±103.8
DM =96.4±46.7	Mean ± SD on day 29 of DM/Q 30/30 mg bid (DM/DX =1.1)^Citation45
DX =89.5±52.3
DM =5.2±5.0	Mean ± SD on day 29 of DM 30 mg bid (DM/DX =0.017)^Citation45
DX =295.9±143.2
Q =150	Mean on day 29 of DM/Q 30/30 bid
Q =80	Median on day 29 of Q 30 bid^Citation45
DM concentrations for cough suppression in CYP2D6 PMs
DM =182–231	Plasma concentrations following chronic dosing for cough in CYP2D6 PMs^Citation98
DM concentrations associated with subjective and psychomotor/cognitive effects
DM =49–168 (mean Cmax)	No significant psychomotor/cognitive effects after single doses in CYP2D6 PMs or EMs + quinidine; some subjective sedation/dysphoria at higher range (>100)^Citation25,Citation35
DM =185–233 (mean Cmax)	Modest psychomotor/cognitive impairment and sedation/dysphoria after single doses in CYP2D6 PMs or EMs + quinidine^Citation25
DM concentrations in patient studies of DM without Q
DM =52–193	Average concentrations observed with tolerable doses in neurosurgery patients^Citation60
DM ≤ 150	No adverse effects in epileptics with chronic dosing (up to 50 mg/q6h)^Citation99
DM ≤ 275	Tolerable plasma concentrations in Huntington’s patients^Citation100
DM =400–500	Concentrations associated with most neurosurgery patients experiencing CNS side effects (ataxia, dizziness, hallucinations), nystagmus^Citation60
DM concentrations in case studies of poisonings and overdose
DM =542	Lowest concentration in postmortem sample, in combination with diphenhydramine, at approximately five times the therapeutic range^Citation101
DM =695–1026	High range of concentrations observed in impaired drivers^Citation102,Citation103
DM =930	Case report of serotonin syndrome^Citation104
DM =1,841–5,244	Other postmortem concentrations associated with fatalities^Citation101,Citation105,Citation106
Therapeutic Q concentrations associated with antiarrhythmia
Q =1,680	Patients with exertional arrhythmia (10 mg/kg oral)^Citation107
Q =2,780 (F)/3,670 (M)	Cmax in healthy volunteers receiving 4 mg/kg IV^Citation108
Q =1,500–5,000	Concentrations associated with torsades de pointes;^Citation37,Citation63 some cases reported “<1,500 ng/mL” but exact concentrations not cited.

Abbreviations: bid, twice daily; C_max, peak plasma concentration; CNS, central nervous system; CYP2D6, cytochrome P450 2D6; EM, extensive metabolizer; IV, intravenous; PBA, pseudobulbar affect; PM, poor metabolizer; SD, standard deviation; q6h, every 6 hours; F, female; M, male.

Figure 1 Summary of comparative improvement changes on the Center for Neurologic Study-Lability Scale score.

Notes: Larger negative scores reflect greater improvement; each set of bars refers to the results in the treatment groups studied Brooks et al,⁴⁵ Panitch et al,⁴⁶ Pioro et al.⁴⁷
Abbreviations: DM, dextromethorphan/dose (mg); PBO, placebo; Q, quinidine/dose (mg).

Table 4 Summary of efficacy studies of DM/Q for PBA

Trial	Dose (mg) (twice daily)		Comparators	Patients	N	Findings
	DM	Q
Brooks et al^Citation45	30	30	DM alone (30 mg) and quinidine alone (30 mg)	ALS	140	After 29 days, DM/Q showed 3.3 and 3.7 point greater improvement on the CNS-LS than DM or Q respectively (P<0.001 both). Complete remission occurred in 52% of DM/Q patients compared to DM (23%) and Q (12%), P<0.001. DM/Q also showed significant improvement on QoL, QoR, and episodes of crying, laughing, or the combination.
Panitch et al^Citation46	30	30	Placebo	MS	150	After 85 days, DM/Q showed a mean change of 7.7, and placebo −3.3 on the CNS-LS (P<0.0001). Complete remission occurred in 20.8% of DM/Q patients compared to 6.9% of placebo (P<0.03).
Pioro et al^Citation47	30 and 20	10	Placebo	ALS and MS	326	After 12 weeks, DM/Q30 showed a mean change of −8.2; DM/Q20 −8.2, and placebo −5.7 on the CNS-LS (P<0.0002). Daily PBA episodes were −46.9% and −49% lower for DM/Q30 and DM/Q20, respectively, compared to placebo (P<0.0001). Remission occurred in 47.3% of DM/Q30, 51.4% of DM/Q20 patients compared to 29.4% in placebo (P<0.001).

Abbreviations: ALS, amyotrophic lateral sclerosis; CNS-LS, Center for Neurologic Study-Lability Scale; DM, dextromethorphan; MS, multiple sclerosis; PBA, pseudobulbar affect; Q, quinidine; QoL, quality of life; QoR, quality of recovery.

Table 5 Adverse event incidence in DM/Q trials for PBA

Adverse event preferred term	Treatment and dose N (%)
ALS patients^Citation45	DM/Q (30/30 mg bid)	DM alone (30 mg bid)	Q alone (30 mg bid)
Dizziness (excluding vertigo)	14 (20%)	5 (15.2%)	1 (2.7%)
Fatigue	13 (18.6%)	3 (9.1%)	0 (0)
Loose stools	0 (0)	3 (9.1%)	3 (8.1%)
Nausea	23 (32.9%)	2 (6.1%)	3 (8.1%)
Somnolence	9 (12.9%)	1 (3.0%)	0 (0)
ALS patients (>10%)^Citation46	DM/Q (30/30 mg bid)	Placebo
Dizziness (excluding vertigo)	20 (26.3%)	7 (9.5%)
Fatigue	11 (14.5%)	6 (8.1%)
Nausea	17 (22.4%)	11 (14.9%)
Weakness	8 (10.5%)	4 (5.4%)
ALS and MS patients^Citation47	DM/Q (30/10 mg bid)	DM (20/10 mg bid)	Placebo
Dizziness (excluding vertigo)	20 (18.2%)	11 (10.3%)	6 (5.5%)
Loose stools/diarrhea	11 (10.0%)	14 (13.1%)	7 (6.4%)
Nausea	14 (12.7%)	8 (7.5%)	9 (7.5%)
Somnolence	11 (10.0%)	9 (8.4%)	7 (6.4%)

Abbreviations: ALS, amyotrophic lateral sclerosis; bid, twice daily; DM, dextromethorphan; DM/Q, dextromethorphan/quinidine; MS, multiple sclerosis; PBA, pseudobulbar affect; Q, quinidine.

Table 6 Summary of potential cardiac and QTc interactions with DM/Q

Drug class/compound	Summary of interaction potential
	Theoretical type of interaction	Pharmacokinetic or pharmacodynamic/safety interaction reported	Risk of QTc prolongationa	Overall assessment of clinical importance	Recommendation
Analgesics
Methadone	P-glycoprotein substrate	Weak PD (25% increase in miosis)^Citation109	Category 3; risk increased at doses >100 mg/day^Citation110	Possible	Supervised start Assess potential for other risk factors for TdP Reduce dose 25%–50%, or substitute with buprenorphine if required
Antiarrhythmics
Amiodarone	CYP3A4 inhibitor	Weak/moderate PK/PD^Citation111^–^Citation113	Category 1	Possible	Supervised start Assess potential for other risk factors for TdP
Procainamide, isopyramide	CYP2D6 substrates	Weak/moderate PK, minimal PD^Citation111,Citation114			Reduce dose if required
Dronedarone	CYP3A4/P-glycoprotein inhibitor	Theoretical; no literature reports
Sotalol, ibutilide, dofetilide, bepridil	None	None
Flecainide	CYP2D6 substrate (minor)	Weak PK, minimal PD^Citation115	Category 3
Mexiletine, propafenone	CYP2D6 substrate	Weak/moderate PK^Citation116^–^Citation118	Category 4
Nifedipine	CYP2D6 substrate	Weak PK, minimal PD^Citation119	Category 4
Antidepressants
Desipramine, amitriptyline, imipramine, nortriptyline, clomipramine	CYP2D6 substrates	Strong to moderate PK (8-fold higher exposure)^Citation23	Category 4	Most likely	Substitute with milnacipran, levomilnacipran, mirtazapine, or desvenlafaxine (depression) Substitute with glycopyrrolate, benztropine, dermal hyoscine, trihexyphenidyl, or atropine (sialorrhea) If substitution not possible, avoid or, if essential, reduce dose 50%–75% and monitor QTc
Antimicrobials
Erythromycin, clarithromycin	CYP3A4 inhibitor	Weak PK (10%–30%)^Citation120	Category 3 (IV)/category 4 (oral)	Possible	Supervised start; if necessary reduce dose or substitute with other antibiotic based on sensitivity
Azithromycin	None	None	Category 4^Citation121		Supervised start; if necessary reduce dose or substitute with alternate antibiotic
Antipsychotics
Haloperidol, clozapine, pimozide	CYP2D6 and/or 3A4 substrates (minor)	Minimal/weak PK^Citation122	Category 3	Most likely	Substitute with olanzapine or quetiapine or reduce dose 50%–75% and monitor QTc
Amisulpride, paliperidone, ziprasidone	None	None		Possible	Supervised start Assess potential for other risk factors for TdP; reduce dose or substitute with olanzapine or quetiapine

Note:

a Based on categories suggested by Redfern et al.⁶¹

Abbreviations: CYP, cytochrome P450; DM/Q, dextromethorphan/quinidine; IV, intravenous; PD, pharmacodynamic; PK, pharmacokinetic; TdP, torsades de pointes; DM, dextromethorphan; Q, quinidine; QTc, corrected QT.

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