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Anesth Pain Med. 2011 July; 1(1): 10–14. Research Article
Comparison of the Efficacy of Adding Clonidine, Chlorpromazine, Promethazine, and Midazolam to Morphine Pumps in Postoperative Pain Farnad Imani 1; Poupak Rahimzadeh 1,*; Seyyed Hamid Reza Faiz 21Department of Anesthesiology and Pain Medicine, Rasoul-Akram Medical Center, Tehran University of Medical Sciences, Tehran, IR Iran 2Department of Anesthesiology, Rasoul-Akram Medical Center, Tehran University of Medical Sciences, Tehran, IR Iran*Corresponding author: Poupak Rahimzadeh, Department of Anesthesiology and Pain Medicine, Rasoul-Akram Medical Center, Tehran University of Medical Sciences, Tehran, IR Iran. Tel/Fax: +98-2166509059. , E-mail: Received: May 5, 2011; Revised: May 13, 2011; Accepted: May 17, 2011
Background: Addicted patients present difficulties for pain management because they have another problem besides their pain. Adding
adjuvants to opioid pumps to intensify quality, control other problems, lengthen analgesia, and reduce side effects has been considered Objectives: The objective of this study was to evaluate the analgesic effects of adding clonidine, promethazine, chlorpromazine, and
midazolam to morphine in patient-controlled intravenous analgesia (PCIA) in orthopedic patients with addiction problems.
Patients and Methods: 90 patients with histories of substance abuse were enrolled in this randomized controlled trial. Patients
were randomly divided into three groups. The first group received 20 mg of morphine sulfate +50 mg of chlorpromazine + 50 mg of promethazine +10 mg of midazolam (M20P). The second group received the first group’s regimen plus 150 micrograms of clonidine (M20PC). The third group received 40 mg of morphine sulfate (M40). A pump with a flow rate of 5 mL/h was chosen. Patients were evaluated every 12 hours, and VAS, VRS, extra opioid usage, nausea and vomiting, and sedation scores were recorded.
Results: Patients’ nausea and vomiting and sedation scores were not statistically different between the three groups. Mean VAS and VRS
scores were found to be statistically lower in the M20PC group than in the other groups. Extra opioid usage between the three groups was statistically lower in the M20PC group than in the other groups. The percentage of patients satisfaction was significantly higher in the M20PC group than in the other two groups.
Conclusions: This study showed that, compared to simply increasing the dose of morphine, adding chloropromazine, promethazine,
midazolam, and clinidine to morphine significantly controlled pain scores and increased treatment satisfaction in addicted patients Keywords: Patient-controlled Analgesia; Addictive Behavior; Clonidine; Morphine; Chlorpromazine 1. Background
individuals may have intermittently high levels of sym- Pain control in addicted patients has always been very pathetic arousal, either as a result of withdrawal or due challenging for pain physicians, especially in cases of to direct sympathetic stimulation by the drugs abused. acute pain in the postoperative period. Because of the un- Such sympathetic stimulation may alter nociceptive predictability in achieving a satisfactory response to any pathways and pain-inhibiting mechanisms in ways that given dose of opioid (1). All pain, whether acute or chron- intensify the pain experience. On the other hand, patients ic, has three experiential components: the physical or no- often fear increased pain when their usage is discontin- ciceptive component, the affective or mood component, ued. Undertreatment of acute pain (3, 4) may be more and the functional component. It is sometimes difficult common in individuals with addictive disorders (5). The for patients with addictive disorders and for their physi- reasons for this appear to be related to fears of causing cians to distinguish which aspect of the patient’s distress or exacerbating addiction through the use of opioids. If a represents pain and which represents opioid craving (2). patient has an opioid addiction, the clinician should not Acute pain is often associated with autonomic responses consider opioid discontinuation until the acute pain sit- such as increases in blood pressure and heart rate, sweat- uation is resolved (6). Therefore, in acute pain service for ing, or skin blanching. Typically, it is accompanied by a addicted patients, opioids are the mainstay of treatment, mood state of anxiety or diminished function. Addicted and they should be used in effective doses. Addicted pa- Implication for health policy/practice/research/medical education:
This study brings new and important light in the field of postoperative pain control for anesthetists, because they could have a great impact on managing pain in addicted patients.
Copyright 2014, Iranian Society of Regional Anesthesia and Pain Medicine (ISRAPM); Published by Kowsar Corp. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work tients often are experts on the drug doses they require to and orthopedic surgery on lower limbs. Exclusion crite- meet their basic dependence needs and the additional ria were any kind of limitation in using studied drugs; levels required to treat their acute pain.
having major cardiac, renal, lung, or liver diseases; using Patient controlled analgesia (PCA) is a useful method another type of analgesia method, and patient refusal. for providing pain relief in opioid-addicted patients be- After the operation and full recovery, a PCA pump was cause their opioid requirement is often higher than aver- connected for pain control. Using a random number age and because it helps to avoid staff–patient confronta- table, patients were randomly divided into three groups. tion over analgesia. Also, the PCA bolus dose may have to The first group received 20 mg of morphine sulfate plus be increased to achieve the desired analgesic effect.
50 mg of chlorpromazine plus 50 mg of promethazine plus 10 mg of midazolam (M20P). The second group re- 2. Objectives
ceived the first group’s regimen plus 150 micrograms Given the difficulties associated with pain medication of clonidine (M20PC). The third group received 40 mg for addicted patients, we used and compared different of morphine sulfate (M40). The rest of the pumps were filled with normal saline up to 100 mL with a flow rate of 5 mL/h. VAS, VRS, sedation, and N&V scores; patient satis- 3. Patients and Methods
faction; and extra opioid usage were measured (Table 1) and recorded in prepared questionnaires at 12, 24, 36, and In a randomized prospective, single-blind, clinical trial 48 hours. Patients with a VAS score above 3 received intra- study, 90 patients with histories of substance abuse were venous injections of 4 mg of morphine. In the cases with selected for orthopedic surgery, signed a letter of con- an N&V score over 3 and respiratory depression and seda- sent, and were accepted into the study. The pain control tion scores over 2, the pump was stopped for 12 hours. The route was PCA via using auto fusers at a flow rate of 5 statistical analysis was carried out with one-way ANOVAs mL/h. Inclusion criteria for study entrance were history in SPSS 11.5. Duncan’s and post-hoc tests were then used to of substance abuse > 1 year, age between 20 and 50 years, Table 1. VAS, VRS, sedation, and N&V scores; patient satisfaction; and extra opioid usage (Pain score from zero to ten)
0 = No pain10 = The worst imaginable pain 1 = No pain2 = Mild pain3 = Moderate pain4 = Severe pain Sedation score
0 = Restless1 = Calm2 = Sleepy3 = Drowsy with response to verbal stimuli4 = Drowsy without response to verbal stimuli5 = Without response to painfull stimuli N&V score c
1 = No N&V2 = Mild nausea without drug need3 = Nausea with drug need4 = No response to one drug attempt Satisfaction score
1 = Excellent2 = Good3 = Moderate4 = Poor 4. Results
day in the three groups were evaluated by Duncan’s and Ninety male patients were included in the study. De- one-way ANOVA tests and were statistically lower in the mographic findings of the study (age, weight, height, M20PC group than in the other groups (p = 0.01 and 0.05, operation duration, opioid type, and opioid usage type) respectively). Extra-opioid usage in the first and second are shown in Table 2. No significant statistical differ- day between the three groups were evaluated using Dun- ence was observed between the three groups. The main can’s tests, and usage was statistically lower in the M20PC findings of this study such as VAS, sedation score, mean group than in the other groups (p = 0.01 and 0.05, re- opioid consumption, and patient satisfaction are pre- spectively). Total opioid consumption was measured and sented in Table 3. The N&V and sedation scores were not evaluated by post-hoc tests, which revealed statistically statistically different between the three groups (p = 0.1 significant differences between the first two groups and and 0.12, respectively). Mean VAS and VRS in the first day the M40 group; specifically, total opioid consumption were evaluated in the three groups by Duncan’s and one- was lower in the M20P and M20PC groups (p = 0.01), but way ANOVA tests and were found to be statistically lower the percentage of patients who were satisfied with their in the M20PC group than in the other groups (p = 0.01 pain medication was higher in the M20PC group than in and 0.05, respectively). Mean VAS and VRS on the second Table 2. Demographic findings in the three study males groups (n = 30)
Morphine (20 mg)
Morphine (20 mg) plus Protocol Morphine (40 mg )(M40) P value
plus Protocol (M20P) plus Clonidine (M20PC)
Age (y) (Mean ± SD)
Height (cm) (Mean ± SD) 172 ± 4
Weight (kg) (Mean ± SD) 71 ± 10
Operation time (h)
(Mean ± SD)
Opioid type (%)

Usage type (%)

Table 3. All findings in the three groups (VAS, VRS, N&V score, sedation, opioid consumption, and patient satisfaction)
Morphine (20 mg) plus Morphine (20 mg) plus Protocol
Morphine (40 mg)
Protocol (M20P)
plus Clonidine (M20PC)
Day 1 (Mean ± SD)
Day 2 (Mean ± SD)
Total (Mean ± SD)
Day 1 (Mean ± SD)
Day 2 (Mean ± SD)
Sedation score
Day 1 (Mean ± SD)

Day 2 (Mean ± SD)
N&V c
Day 1 (times) (Mean ± SD)
Day 2 (times) (Mean ± SD)
Extra opioid
Day 1 (mg) (Mean ± SD)
Day 2 (mg) (Mean ± SD)
Total opioid usage (mg)
(Mean ± SD)
Patient satisfaction (%)

5. Discussion
nificantly lower than in the other two groups, and total opioid consumption dosage was much lower, especially Chronic use of opioids, alcohol, cocaine, and other in comparison with the M40 group. Still, patient satis- drugs has been reported to induce various changes in faction with the drug regimen was higher in the M20PC central opiate receptors and in norepinephrine, sero- group. Morphine is a strong mu-agonist with long-acting tonin, dopamine, and GABA availability, altering neuro- effects, playing a major role in treating the pain of ad- modulation of brain-reward mechanisms. Such receptor dicted patients. Chlorpromazine, a phenothiazine with and neurotransmitter changes may affect modulation of antipsychotic and anti-vomiting effects, (15) has been nociception as well (7). Effective pain-treatment interven- used for acute migraine attacks. Chlorpromazine has also tions in addicted patients vary according to the physi- been used as a useful adjuvant for treating withdrawal ologic causes of pain, other symptoms, and distresses symptoms in heroin-addicted patients. Also, research associated with pain and their psychological problems. has shown that chlorpromazine plays a substantial role Patients in certain situations, such as those who take in craving decline in addicted patients by inhibiting the other nonopioid drugs unrelated to their addiction, may postsynaptic dopaminergic mesolimbic receptors (16- have special needs that should be considered when de- 18). Promethazine is useful in treating nausea, vomiting, signing their treatment therapy (8). Creating effective and motion sickness. It has been used for chronic pain pain management is not acheiveble by increasing opi- attacks. Additionally, promethazine and some antihis- oid dosage alone because such an approach is not only taminic drugs have been found to play effective roles in unable to improve patient satisfaction or comfort or to treating withdrawal symptoms (19, 20). Midazolam is a control their symptoms, but it also might make them short-acting benzodiazepine and has central analgesic prone to further side effects and of course opioid toler- effects by inhibiting glutamate receptors in cord. Also, ance. For these reasons, previous research has strongly animal studies have revealed the effects of benzodiaz- recommended to use adjuvant therapy in pain control of epines in the prevention of opioid tolerance (especially patients with substance abuse (9). Therefore, in treating morphine) and drug dependency (21). Although the an- pain in addicted patients, multiple medications may be algesic role of alpha-2 adrenoceptor agonists in opioid used to reduce pain and to manage distressing sequelae dependency has been described in the literature (8), few and perpetuating factors, such as sleep disturbance, rest- clinicians appear to make regular use of this approach. lessness, anxiety, depression, and craving (10-12). Some The membrane-based opioid receptor and the alpha-2 medical professionals who specialize in medication for receptor share similarities in both being part of a large addicted patients have described a “syndrome of pain fa- superfamily of G-protein-coupled receptors. Activation cilitation or disinhibition” as occurring in the presence of the G-protein-coupled receptor initiates interaction of a painful and actively addictive disease. This situation with an inhibitory G-protein, resulting in a reduction in is characterized by a diffuse anatomic pattern of a rela- neurotransmission, which is expressed in the individual tively constant level of pain and a lack of response to any as the quietening that is typically seen after morphine intervention other than the administration of the chemi- or clonidine use (9). Clonidine provides analgesia after cal on which the individual is dependent (13, 14). Changes surgery or trauma and is particularly useful when opioid in opiate receptors and in endogenous systems of pain in- withdrawal may be complicating the situation, acting hibition definitely play important roles in this observed synergistically with any background opioid but conve- phenomenon in some individuals who are chronically niently not promoting nausea, vomiting, or respiratory dependent (7). The results of the present study showed depression. Also, clonidine could decrease craving in that, instead of simply increasing the dosage of mor- addicted patients (22). Heavy users of opioids may dem- phine, using morphine in addition to chlorpromazine, onstrate a degree of resistance to parenteral clonidine, promethazine, midazolam, and clinidine significantly but a 2-4 µg/kg intravenous dose of the drug will usually controlled pain scores and increased patient satisfac- produce a noticeable quietening and sedation of the pa- tion without having notable side effects. The VRS and tient in 5 to 10 minutes (8). On the other hand, patient- VAS scores of the patients in the M20PC group were sig- controlled-analgesia pumps have many advantages that make their use ideal for addicted patients. In particular, 9. Weaver MF, Schnoll SH. Opioid treatment of chronic pain such pumps can prepare adequate serum concentration in patients with addiction. J Pain Palliat Care Pharmacother. levels in the therapeutic window range, result in less 2002;16(3):5–26.
10. Lewis NL, Williams JE. Acute pain management in patients re- fluctuation in the serum level of the pain medication, ceiving opioids for chronic and cancer pain. Contin Educ Anaesth create better overall analgesic effects, and lower the total Crit Care Pain. 2005;5(4):127.
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ditional analgesia. Ideally, a multimodal approach, with 13. Rapp SE, Ready LB, Nessly ML. Acute pain management in pa- tients with prior opioid consumption: a case-controlled retro- appropriate combinations of local anesthesia, alpha-2 spective review. Pain. 1995;61(2):195–201.
agonists, anti-histaminic, benzodiazepines, antidopa- 14. Mitra S, Sinatra RS. Perioperative management of acute pain in minergics, ketamine, anti-inflammatory analgesics, and the opioid-dependent patient. Anesthesiology. 2004;101(1):212–27.
15. Mystakidou K, Befon S, Liossi C, Vlachos L. Comparison of tropise- paracetamol is advocated (23, 24). Using higher bolus tron and chlorpromazine combinations in the control of nausea doses with PCA and shorter lock-out intervals is a recom- and vomiting of patients with advanced cancer. J Pain Symptom mended strategy (25). Looking at this issue from different Manage. 1998;15(3):176–84.
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able choice if further studies confirm the present study’s 17. Richter PA, Burk MP. The potentiation of narcotic analgesics with finding or provide similar results for other drugs in the phenothiazines. J Foot Surg. 1992;31(4):378–80.
same family. In summary, considering all of the above 18. Kelly AM, Ardagh M, Curry C, D'Antonio J, Zebic S. Intravenous mentioned findings, it seems reasonable and quite wor- chlorpromazine versus intramuscular sumatriptan for acute migraine. J Accid Emerg Med. 1997;14(4):209–11.
thy to add chlorpromazine, promethazine, midazolam, 19. Koyuncuoglu H, Saydam B. The treatment of heroin addicts and clonidine to morphine for suitable control of pain with dextromethorphan: a double-blind comparison of dextro- and other problems of addicted patients in acute pain methorphan with chlorpromazine. Int J Clin Pharmacol Ther Toxi- col. 1990;28(4):147–52.
management. The authors of this article advocate more 20. Steen RR, Meeks CM, Mc Gowan Je, Sutton HL, Healy RJ, Cryan JP. research and trials on this issue to identify the most ef- Narcotic addition; preliminary report on the effects of dimenhy- fective drug regimen for patients with substance-abuse drinate (dramamine) on withdrawal symptoms. N Y State J Med. 1954;54(2):267–8.
21. Tejwani GA, Rattan AK, Sribanditmongkol P, Sheu MJ, Zuniga J, Acknowledgements
McDonald JS. Inhibition of morphine-induced tolerance and de- pendence by a benzodiazepine receptor agonist midazolam in We would like to acknowledge all of our colleagues in the rat. Anesth Analg. 1993;76(5):1052–60.
the Department of Pain who helped us with this project.
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Financial support
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