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: poupak_rah@hotmail.com
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 (%) Natural Usage type (%) Inhalation Injection Table 3. All findings in the three groups (VAS, VRS, N&V score, sedation, opioid consumption, and patient satisfaction) Variables Morphine (20 mg) plus Morphine (20 mg) plus Protocol Morphine (40 mg) Protocol (M20P) plus Clonidine (M20PC) VAS a Day 1 (Mean ± SD) Day 2 (Mean ± SD) Total (Mean ± SD) VRS b 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,
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fluctuation in the serum level of the pain medication,
ceiving opioids for chronic and cancer pain. Contin Educ Anaesth
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haviour. Aust Fam Physician. 2004;33(12):1009–12.
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12. Alford DP, Compton P, Samet JH. Acute pain management for
consensus in the field is to maintain regular provision of
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appropriate combinations of local anesthesia, alpha-2
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paracetamol is advocated (23, 24). Using higher bolus
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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.
22. Iocolano CF. Perioperative pain management in the chemically
dependent patient. J Perianesth Nurs. 2000;15(5):329–44. Financial support
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generation antipsychotic drugs: a validity of the serotonin-dopa-
mine hypothesis. Prog Brain Res. 2008;172:199–212.
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tolerance to daily heroin administration: an apparent phenom-
Conflict of interest
enon associated with enhanced pain sensitivity. Neuroscience.
1999;89(3):631–6.
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Clinical course of sepsis in children with acute leukemia admitted to the pediatric intensive care unit* Kanakadurga Singer, MD, MA; Perla Subbaiah, PhD; Raymond Hutchinson, MD;Folafoluwa Odetola, MD, MPH; Thomas P. Shanley, MD Objective: To describe the clinical course, resource use, and inotropic and/or vasopressor drugs ( p ؍ .01), and renal replace- mortality of patients wi