Table 7Summary of Findings of Included Non-Randomized Studies

Main Study FindingsAuthor’s Conclusion
Isbister et al. 201719
Acute Clonidine Ingestion (n = 108)
  • GCS (maximum score of 15 indicates a fully awake patient):
    • GCS < 15 in 73 patients (68%)
      • Clonidine alone:22 patients (55%)
      • Clonidine with co-ingestant: 51 patients (75%)
    • No significant association with dose (P = 0.40)
    • Coma (GCS < 9) in 10 patients (9%)
      • Clonidine alone: 2 patients (5%)
      • Clonidine with co-ingestant:8 patients (12%); all cases included at least a benzodiazepine
  • Miosis in 31 (29%) patients:
    • Clonidine alone: 10 patients (25%)
    • Clonidine with co-ingestant: 21 patients (31%)
  • Hypothermia (temperature <35°C) in 11 patients (10%)
  • Minimum heartrate (HR):
    • Median of 48 bpm (IQR of 40 to 57 bpm)
      • Clonidine alone:48bpm (40 to 62 bpm)
      • Clonidine with co-ingestant: 47 bpm (40 to 55 bpm)
    • Range of 32 to 88 bpm
    • Significantly associated with clonidine alone dose; slope of −0.002 ± 0.001 bpm/µg; P = 0.02
  • Sinus bradycardia(HR < 60 bpm):
    • 82 patients (76%):
      • Clonidine alone:27 patients (68%)
      • Clonidine with co-ingestant: 55 patients (81%)
    • Median onset of 2.5 hours post-ingestion
    • Median duration of 20 hours
    • 41% with bradycardia were discharged still bradycardic
  • Minimum systolic blood pressure (BP):
    • Median of 96 mm Hg
    • No significant association with dose (P value not reported)
  • Hypotension (systolic BP < 90 mm Hg):
    • 26 patients (24%)
    • Clonidine alone:
      • 10 patients (25%)
      • Median onset of 4.2 hours
      • Median duration of 11 hours
    • Clonidine with co-ingestant:
      • 16 patients (24%)
      • Median onset of 8 hours
      • Median duration of 2.8 hours
  • Severe hypertension (systolic BP > 180 mm Hg) in 2 patients (2%); both patients took co-ingestant
  • Early hypertension (not defined) in 3 patients (3%) with clonidine doses of 8, 10, and 12 mg
  • No arrhythmias or deaths
  • 26 patients (24%) admitted to ICU
  • Intubation and ventilation:
    • 12 patients (11%)
    • Clonidine alone:
      • 2 patients (5%)
      • 5 mg dose in one case; aggression in other case
    • Clonidine with co-ingestant:
      • 10 patients (15%)
      • 6 patients (9%) in coma
  • Treatment:
    • Activated charcoal in 24 patients (22%)
    • Naloxone in 23 patients (21%)
    • Atropine in 8 patients (7%)
    • Clonidine alone:
      • Activated charcoal in 10 patients (25%)
      • Naloxone in 7 patients (18%)
      • Atropine in 4 patients (10%)
    • Clonidine with co-ingestant:
      • Activated charcoal in 14 patients (21%)
      • Naloxone in 16 patients (24%)
      • Atropine in 4 patients (6%)

Staggered Clonidine Ingestions (n = 11)
  • Bradycardia (HR < 60 bpm) in 10 patients (91%)
  • Hypotension (systolic BP < 90 mm Hg) in 3 patients (27%)
  • GCS < 15 in 4 patients (36%)
  • No arrhythmias or deaths
  • 1 (9%) patient admitted to ICU for cardiac monitoring
  • Naloxone treatment in 2 patients (18%)
  • Atropine treatment in 1 patient (9%)
“Our study found that clonidine causes persistent but not life-threatening clinical effects including bradycardia and CNS [central nervous system] depression. Although these initially appear to be clinically significant, they are unlikely to predict a poor patient outcome.” p. 191

“Bradycardia was significantly associated with the dose ingested in the clonidine alone overdoses, and developed within hours of ingestion in both clonidine alone and clonidine with co-ingestant over doses. Bradycardia lasted for 24 to 48 h [hours] and was the same for clonidine alone and clonidine with co-ingestant overdoses. In contrast, hypotension was not dose-related, had a later and far more variable onset and variable duration. The onset and duration of hypotension was also different between clonidine alone and clonidine with co -ingestant overdoses.” p. 190-191
Detweiler et al. 201617
No response (no change in combat nightmares), partial response (decrease in frequency and severity of combat nightmares), and full response (total suppression of combat nightmares) to medications prescribed for PTSD combat nightmares:

Clonidine (27 medication trials):
  • No response in 10 trials (37%); dosages of 0.1 to 4 mg/day
  • Partial response in 17 trials (63%); dosages of 0.1 to 2 mg/day
  • No patients had a full response

Prazosin (106 medication trials):
  • No response in 54 trials (51%); dosages of 1 to 20mg/day
  • Partial response in 46 trials (43%); dosages of 1 to 10 mg/day
  • Full response in 6 trials (6%); dosages of 1 to 10 mg/day

Risperidone (81 medication trials):
  • No response in 19 trials (23%); dosages of 0.25 to 5 mg/day
  • Partial response in 41 trials (51%); dosages of 0.5 to 6 mg/day
  • Full response in 21 trials (26%); dosages of 0.5 to 3 mg/day

Quetiapine (72 medication trials):
  • No response in 36 trials (50%); dosages of 12.5 to 500 mg/day
  • Partial response in 30 trials (42%); dosages of 25 to 800 mg/day
  • Full response in 6 trials (8%); dosages of 6 to 287 mg/day

Terazosin (26 medication trials):
  • No response in 10 trials (39%); dosages of 1 to 20 mg/day
  • Partial response in 16 trials (61%); dosages of 2 to 50 mg/day
  • No patients had a full response

Trazodone (22 medication trials):
  • No response in 14 trials (64%); dosages of 50 to 200 mg/day
  • Partial response in 7 trials (32%); dosages of 50 to 300 mg/day
  • Full response in 1 trial (4%); dosage of 200 mg/day

Mirtazapine (20 medication trials):
  • No responsein 10 trials (50%); dosages of 7.7 to 30 mg/day
  • Partial response in 9 trials (45%); dosages of 7.5 to 30 mg/day
  • Full response in 1 trial (5%); dosage of 15 mg/day

Olanzapine, aripiprazole, ziprasidone, perphenazine, prazosin and trazodone, and prazosin and quetiapine were prescribed in ≤ 5 trials.		“The findings of this comparative study strongly suggest the need for additional investigation of multiple medications. In addition, the positive results for risperidone at this VA [Veterans Affairs] could suggest its use as the first treatment choice for PTSD [post-traumatic stress disorder] nightmares, since positive results occur rapidly at a limited dose range. However, this choice would need to be weighed against the only moderately less successful clonidine and terazosin and their lower risk of adverse effects. Further study of this option is warranted.” p. 20
Mannelli et al. 201318
Nicotine-Dependent In-Patients of an Opioid Detoxification Program (N = 96)
  • Smoking (cigarettes/day) was significantly reduced in naltrexone/clonidine group vs. naltrexone alone group; P < 0.02
  • Probability of smoking less than the daily average was not significantly higher in placebo/clonidine group vs. placebo alone group; RR = 1.2; P = 0.5
  • Cigarette craving:
    • Significantly reduced in naltrexone/clonidine group vs. naltrexone alone group; P < 0.01
    • Not significantly reduced in placebo/clonidine group vs. placebo alone group; P < 0.13
    • “Positive” craving item scores were significantly reduced in naltrexone/clonidine group vs. naltrexone alone group (P < 0.03), indicating less craving associated with the rewarding properties of smoking
    • “Negative” craving item scores were significantly reduced in naltrexone/clonidine group vs. naltrexone alone group (P < 0.03), indicating less craving associated with relief from negative effects
  • No medication-related adverse events
“Despite its limitations, this study suggests that VLNTX [very low dose naltrexone] + low dose clonidine is well tolerated and associated with improved smoking behaviors in OA [opioid addiction]. Further investigations should test the effectiveness of this pharmacological combination for smoking cessation in patients with or without comorbid substance abuse disorders.” p. 1711

BP = blood pressure; bpm = beats per minute; GCS= Glasgow coma score; HR = heart rate; ICU = intensive care unit; PTSD = post-traumatic stress disorder; RR = risk ratio.

From: Clonidine for the Treatment of Psychiatric Conditions and Symptoms: A Review of Clinical Effectiveness, Safety, and Guidelines

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Clonidine for the Treatment of Psychiatric Conditions and Symptoms: A Review of Clinical Effectiveness, Safety, and Guidelines [Internet].
Chiu S, Campbell K.
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