141
Pain, 43 (1990) 141-148 Elsevier
PAIN 01671
Clinical Section Intrathecal methadone: a dose-response study and comparison with intrathecal morphine 0.5 mg * Louis
Jacobson,
Department
Charles
Chabal,
Michael
C. Brody
a, Richard
J. Ward
and
Loretta
Wasse
of Anesthesiology, University of Washington School of Medicine, and VA Medical Center, Seattle, WA 98108 (U.S.A.). and o Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15213 (U .%A.) (Received
20 December
1989, revision received and accepted
31 May 1990)
Summary
The analgesic and adverse effects of intrathecal methadone 5 mg, 10 mg and 20 mg were assessed and compared with intrathecal morphine 0.5 mg. The study was conducted on 38 patients who underwent total knee or hip replacement surgery. The intrathecal opioid was administered at the end of surgery and assessments began 1 h thereafter and continued for 24 h. Pain measurements, supplementary analgesia requirements, and adverse effects were recorded. Intrathecal morphine 0.5 mg provided effective and prolonged analgesia. Intrathecal methadone 5 mg, 10 mg, and 20 mg produced good analgesia of 4 h duration. Thereafter the median pain scores with intrathecal methadone were consistently higher (worse) than those with intrathecal morphine (P < 0.05). The time to the onset of discomfort severe enough to require supplemental morphine was longer after intrathecal morphine than following methadone (15 h with morphine 0.5 mg; 6.25 h, 6.5 h and 6 h with methadone 5 mg, 10 mg, and 20 mg respectively: P < 0.05). Central nervous system depression manifesting as respiratory depression, hypotension, and excessive drowsiness occurred in 3 of 8 patients injected with methadone 20 mg intrathecally. Generalized pruritus, nausea, vomiting, and urinary retention were common and equally distributed among the treatment groups. We conclude that both intrathecal morphine 0.5 mg and methadone 5, 10, and 20 mg provide excellent analgesia but that morphine has a more prolonged effect. Methadone 20 mg produced unacceptable side effects. Clinical evidence for rostra1 spread of methadone within the CSF, as indicated by facial itching and excessive drowsiness, was less apparent with 5 mg than with 10 and 20 mg. Various explanations for the observed differences between the drugs are discussed. Key words Analgesia,
postoperative;
Opiates,
methadone,
morphine;
Introduction An alternative intrathecal opioid to morphine is desirable because intrathecal morphine is associated with a high incidence of side effects such as pruritus, nausea, vomiting and urinary retention
* Work performed
at the Seattle VA Medical
Center.
Correspondence to: Louis Jacobson, M.D., Anesthesiology Service (112A), VA Medical Center, 1660 South Columbian Way, Seattle, WA 98108, U.S.A.
03043959/90/%03.50
0 1990 Elsevier Science Publishers
Anesthetic
techniques,
spinal;
Opiates,
intrathecal
[18]. Sustained respiratory depression can also occur with intrathecal morphine administration [18]. A satisfactory alternative should provide profound and prolonged analgesia without adverse effects. Methadone is a lipophilic opioid which is rapidly cleared from the cerebrospinal fluid (CSF) [32]. With doses of 2-5 mg, little if any is available to brain-stem opioid receptors [25,32]. Therefore, intrathecal methadone could produce analgesia by a predominantly spinal mechanism, resulting in fewer supraspinal adverse effects than with intrathecal morphine. Intrathecal methadone 1 mg, however, provides inferior postoperative analgesia
B.V. (Biomedical
Division)
to morphine 0.5 mg and 1 mg which produce profound and prolonged analgesia [ 191. Methadone possesses physicochemical properties which confer on it the ability to provide prolonged analgesia when given intravenously in large doses of 20 mg or greater [ll 13.15,39]. Sufficient quantities of methadone injected intrathecally might also be capable of producing prolonged analgesia. Therefore, in order to determine whether larger doses of methadone could provide satisfactory, safe and prolonged postoperative analgesia, we compared intrathecal methadone 5 mg, 10 mg and 20 mg with intrathecal morphine 0.5 mg, an effective and safe dose [18.19].
Methods The project was approved by our Human Subjects Review Board and the Federal Drug Administration (FDA). Written informed consent was obtained from each patient preoperatively. Subjects for the study were 38 men scheduled for total knee or hip replacement surgery. Relevant patient data are outlined in Table I. The study was conducted in 3 consecutive stages. Initially the subjects were divided into 2 groups: (1) intrathecal morphine 0.5 mg (n = lo), and (2) intrathecal methadone 5 mg (n = 10). The patients were randomly assigned to a treatment group and the drug was administered, over approximately 1 min, in a double-blind manner. Commercially available preservative-free morphine (Duramorph) 1 mg/ml and methadone (Dolophine) 10 mg/ml were used, and all injectates were standardized to a volume of 1 ml with sterile water. Stage 2 involved the administration of intrathecal methadone 10 mg (1 ml) to 10 consecutive patients under single-blinded (to the patient) and controlled conditions. In the final phase (stage 3). methadone 20 mg (2 ml) was injected intrathetally to 8 patients under identical conditions to stage 2. The study was terminated after adverse effects occurred in 3 of 8 subjects who received intrathecal methadone 20 mg. No premeditation, intraoperative opioids or long acting sedatives were given. Except for these constraints the type of anesthesia was at the
anesthesiologist’s discretion and involved inhala tional general anesthesia (21 patients), lumbar epidural anesthesia (5 patients) and subarachnoid anesthesia (12 patients: see Table I). The average duration of surgery was 3.5 h. The intrathecal opioid was injected at the end of the surgical procedure. Systemic opioids were withheld until requested or recommended in the postoperative period, when incremental small doses of intravenous morphine were given until satisfactory analgesia (nil or mild discomfort) was obtained. Subsequently, morphine was administered intramuscularly according to the patients’ requirements. The time at which initial discomfort occurred was recorded. as were the times when supplementary morphine analgesia was given. Assessments during stage 1 (morphine 0.5 mg versus methadone 5 mg) were conducted by an investigator who was unaware of the constituents of the subarachnoid injection. Thereafter, fat methadone 10 mg and 20 mg, the assessor knew the injectate contents. The assessments commenced 1 h after the injection and continued for 24 h. Observations were conducted at hourly intervals for the first 6 h after the opioid injection. Further assessments were done at 8 h, 18 h and 24 h post injection. Pain was assessed by verbal patient response using a numerical pain rating system (0 = no pain to 10 = worst pain imaginable) [6,20]. Adverse effects monitored included pruritus. nausea, vomiting. excessive sedation, respiratory depression and urinary retention requiring catheterization. Assessments of sedation and respiration were done with the subjects at rest and undisturbed prior to making the remaining observations. Sedation was assessed using a rank scale A to D where A = awake and alert; B = dozing and easily roused; C = dozing and roused with difficulty; and D = unrousable/unresponsive. Patients in categories C and D were considered to be excessively sedated. Ventilation was gauged with repeated measurements of arterial blood gas tensions performed with the subjects undisturbed at each assessment interval upto and including 8 h. All the patients had indwelling arterial cannulae from which blood samples were easily and painlessly withdrawn. Statistical analysis of differences in times until
143
supplementary morphine was needed and the numerical pain scores were accomplished using the Kruskal-Wallis analysis of variance by ranks [lo]. Qualitative data were analyzed by the Fisher Exact Probability test. A probability of less than 0.05 (P < 0.05) was considered statistically significant.
TABLE
II
MEDIAN
PAIN SCORE
Data are median Time (h) after opioid injection
Results
2
There were no significant differences between the groups in age, weight or height (Table I). The operative procedures and anesthetic techniques were equally represented in the different age groups (Table I). Both intrathecal morphine and methadone provided excellent analgesia for the first 4 h post injection (P -c 0.05). Thereafter, the median pain scores with intrathecal morphine were consistently lower than those with intrathecal methadone 5 mg, 10 mg and 20 mg (P > 0.05; Table II). The time to onset of discomfort severe enough to require supplemental morphine was longer with intrathecal morphine than intrathecal methadone TABLE
I
CLINICAL Data
DATA
are median
with interquartile Dose of intrathecal
Methadone
0.5
5
10
Height
(cm)
Surgical Hip
opioid (mg)
Morphine
n Age (years) Weight (kg)
range in parentheses.
(59-72) 66 86 (80-115) 175 (170-184)
procedures
10 10
(61-71) 65 87 (68-95) 176 (169-187)
20
10 (42-74) 65 83 (744100) 182 (1788185)
8 (::-73) 75 (54-85) 172 (170-175)
4
6
3
replacement
5
6
4
5
General Spinal Epidural
4 5 6 8
(no. of patients) 6 5 3 3 1 2
5 3 2
5 3 0
O-10)
opioid (mg)
Methadone 5 0
(o-0.25) 0
10
20
0 _
0 _
0
0 _
(O-2)
(O-2) 0 (O-0.5) 0
(O-l) 0 (O-3)
1 (O-5.5) 1
(O-l) 0 (O-0.75) 0 (O-0.75) 0 (O-0.5)
(O-6.5) 3 (l-5.5) 4 (l-5.5) 3.5
(O-7) 2.5 (O-6.5) 3 (0.5-6) 5.5
(O-4) 1.5
(l-5)
(2-7)
(O-5)
0 _
0.5
(O-5) 4.5 (O-6) 3
(P < 0.05; Table III). The median time to initial supplementation analgesia was 15 h with morphine 0.5 mg, and 6.25 h, 6.5 h and 6 h following intrathecal methadone 5 mg, 10 mg and 20 mg respectively. The total amount of supplementary morphine needed in the 24 h following the subarachnoid injection was significantly less in patients receiving morphine than methadone intrathecally (P < 0.05; Table III). On average 5.5 mg of supplemental morphine was needed following intrathecal morphine 0.5 mg as compared to 23 mg, 22 mg
TABLE
III
ANALGESIA:
NEED
Data are median
FOR SUPPLEMENTAL
with interquartile
Time to first analgesia (h) Amount of suppl. morphine in 1st 24 h (mg)
opioid (mg)
Morphine
Methadone
0.5
5
10 6.25
(::_27) 5.5 (O-24)
OPIOIDS
range in parentheses.
Dose of intrathecal
5
technique
Morphine ~ 0.5
(no. of patients)
replacement Knee
Anesthetic
3
SCALE
range in parentheses.
Dose of intrathecal
0.5 (O-2.5) 0.5
1
(VERBAL
with interquartile
(4-9) 23 (9-33)
6.5 (5-10) (Z-50)
20 6 (4-10) $45)
144
and 30 mg for intrathecal methadone 5 mg, 10 mg and 20 mg respectively. Respiratory depression (p,CO, > 50 mm Hg) occurred only with intrathecal methadone 20 mg (P < 0.05; Table IV). The median paC02 levels with methadone 20 mg were consistently elevated from 1 to 3 h post injection (P < 0.05; Fig. 1). These data do not include values following naloxone therapy. The median paCOz remained within normal limits after methadone 5 mg and 10 mg as well as morphine 0.5 mg. Pruritus was frequently encountered in each group (P > 0.05; Table IV). Following methadone the itch was apparent by 1 h post injection and had usually receded at 4 h or shortly thereafter. lntrathecal morphine was associated with itching of slower onset and longer duration. The pruritus was minor and required no treatment. Urinary retention, nausea and vomiting were common in all the treatment groups (P > 0.05;Table IV). There was no evidence of motor or sensory impairment associated with either intrathecal morphine or methadone. There was a tendency for excessive drowsiness (levels C and D) to manifest more commonly in the methadone 10 mg and 20 mg groups (Table IV). This was, however, only a trend and was not statistically significant (P > 0.05).
TABLE
IV
ADVERSE
EFFECTS
Data are the number of patients manifesting the adverse effect (numerator) and the total number (denominator). Those patients with elective preoperative urinary bladder catheterization were excluded. Dose of intrathecal Morphine
Pruritus Facial pruritus Nausea/vomiting Resp. depression (p,CO, > 50 mm Hg) Excessive drowsiness Urinary retention requiring catheterization
opioid (mg)
Methadone
0.5
5
10
20
6/10 6/10 6/10
6/10 O/IO l/10
8/10 5/10 3/10
5/8 5/x 4/8
O/10 o/10
O/10 l/10
O/10 4/10
4/8 3/8
6/7
5/9
6/8
5/l
““;
6
Time (hours) after intrathecal
8 injection
Fig. 1. The effect of intrathecal methadone and morphine on paCO,. Data are median p,CO, with quartile deviation represented by the bars.
Central nervous system depression comprising hypotension, respiratory depression and excessive sedation (levels C and D) occurred in 3 of 8 patients who received intrathecal methadone 20 mg. This appeared 5-10 rnin post injection with excessive drowsiness and hypotension. All 3 patients were clinically normovolemic and maintained a constant heart rate throughout the episode. Phenylephrine infusion rapidly restored and maintained the blood pressure. Apnea supervened in the 3 patients at 10 min, 30 min and 45 min respectively. A single dose of naloxone (SO- 120 pg) administered in 40 pg aliquots permanently restored clinically satisfactory spontaneous ventilation without reversal of analgesia.
Discussion
Intrathecal methadone was as potent trathecal morphine thereby confirming the data which suggests that 8.5 mg methadone provide analgesia equivalent to morphine [26]. Information obtained from intrathecal
as inanimal should 0.5 mg meth-
145
adone 1 mg [19] as well as the 5 mg, 10 mg, and 20 mg, used in this study, indicate that the minimal effective dose of intrathecal methadone lies between 1 mg and 5 mg. Although clinical potency did not differ between methadone and morphine, duration of action did. There were big differences in the duration of analgesia and the amount of supplemental morphine required between the morphine group and all the methadone groups. Intrathecal morphine reliably produced profound and prolonged analgesia, whereas intrathecal methadone was of shorter duration. Intrathecal methadone 20 mg provided neither the prolonged analgesia attributable to intrathecal morphine [5,18,19,31] nor the extended analgesia associated with the same dose of intravenous methadone (20 mg) [ll-13,151. Lipid solubility is an important determinant of CSF elimination and duration of action of opioids administered intrathecally. A CSF reservoir of opioid is important in maintaining an adequate concentration gradient to the spinal opioid receptors. Morphine is the least lipophilic of the clinically used opioids. Following lumbar intrathecal administration, a highly ionized and hydrophilic drug such as morphine remains in the CSF and results in high and sustained CSF morphine concentrations [21,22,28, 31,371. High blood concentrations are not associated with intrathecal morphine therapy [4]. Intrathecal methadone is rapidly cleared from the CSF [25,32] and there is no reservoir for maintaining CNS concentration over prolonged periods. Large doses of lipophilic opioids injected intrathetally are rapidly absorbed into the plasma [24,29] but the ensuing blood levels are usually insufficient to induce systemic analgesia [8,24,39]. Intrathecal methadone may enter the circulation at a lower rate than the systemic clearance rate. Consequently, intrathecal methadone probably reached the circulation in insufficient quantities to manifest prolonged analgesia. The fat-rich areas of the CNS possibly acted as a reservoir for large amounts of methadone which attached to opioid receptors and/or were sequestered in the lipid layers by non-specific binding [26,40]. The CNS storage of methadone might have constituted a slow release mechanism for methadone to access the circulation in subanalgesic concentrations.
Morphine and methadone are both mu opioid receptor agonists which have similar, relatively high, affinity for the mu receptor and little for the other opioid receptors [26]. Consequently, it is unlikely that potentially confounding variables such as mu receptor affinity and affinities for different opioid receptor subtypes played a clinically significant role. Other factors such as rate of metabolism, molecular size, and molecular shape also probably exerted little influence [27]. However, there is no clinical evidence to support these contentions and it should be acknowledged that morphine and morphine-6glucuronide have some affinity for delta receptors. Limitations of the study should be acknowledged. Its conditions precluded the assessment of the onset of analgesia. Another shortcoming was that the study was not simultaneously doubleblinded for all the doses of intrathecal methadone. Methadone 20 mg (10 mg/ml) is a 2 ml solution. All the preceding drugs and doses were administered in a 1 ml volume. It is conceivable that the volume of the 20 mg injectate contributed to the predilection for rostra1 supraspinal effects. However, previous studies with intrathecal morphine 0.3, 1 and 2.5 mg all administered in 2.5 ml showed that the dose and not the volume (2.5 ml) was important in producing adverse supraspinal effects [18]. Therefore, it is likely that the supraspinal effects of methadone 20 mg in 2 ml were mainly the result of the dose and not the volume of the injectate. The FDA, the Human Subjects Review Board, and common sense dictated that we proceed cautiously because of the limited use of intrathecal methadone in both animals [32] and humans [19,25]. Each preceding dose had proven safe and comparable large doses of intrathecal meperidine [9,24,29] and intrathecal morphine [4,34,35] had been safely administered to humans. Central nervous system depression comprising hypotension, drowsiness, and respiratory depression occurred in 3 of 8 patients following intrathecal methadone 20 mg. Spinally administered opioids may exert physiological actions on the cardiovascular system that are not observed at concentrations reached by systemic doses [42]. Opioid peptides and opiate receptors have been
146
localized in brain structures involved in the central regulation of hemodynamic as well as respiratory functions [1,2,7,36]. Hypotension and bradycardia have been observed following opioid injection into the cisterna magna or fourth ventricle of animals [3,23]. The hemodynamic effects of intrathecal methadone 20 mg may be due to its action on central cardiovascular regulation centers. The most plausible explanation for the rapid and profound CNS depression associated with intrathecal methadone 20 mg is direct depression of the cardio-respiratory areas in the brain-stem by large concentrations of methadone which migrated rostrally within the CSF. Evidence is available for minimal vascular uptake, rapid dural transfer into CSF and rapid rostra1 movement in the CSF of lipid-soluble opioids administered epidurally [16,17]. The average time to the maximum cervical CSF fentanyl concentration following lumbar epidural administration was 22.5 min, but in 2 patients peak levels were reached 10 min after irrjection [77]. Epidural fentanyl 200 pg inhibits ventilation from 30 to 120 min post injection probably as a consequence of cephalad migration of fentanyl in CSF [30]. These observations correlate with the pattern of supraspinal adverse effects noted with methadone 20 mg in this study. Furthermore, rapid unpredictable cephalad spread of spinal local anesthetics occurs regularly in routine clinical practice, and total spinal anesthesia manifesting within 10 n-tin of injection of 15 mg of spinal bupivacaine has been reported (331. It is therefore apparent that opioids and local anesthetics injected in the lumbar intrathecal space can rapidly reach supraspinal areas of the CNS as a result of passive CSF flow, thereby providing circumstantial evidence to support our explanation of the adverse effects of intrathecal methadone 20 mg. Lipophilic opioids injected intrathecally are absorbed into plasma [22,24,28,37]. Measurable amounts of methadone, morphine, and meperidine rapidly appear in the blood following high dose intrathecal administration [4.24,25,29]. Consequently rapid intravascular uptake and supraspinal distribution via the blood may be involved in the transport of large quantities of methadone to the brain-stem. However, similar cardiovascular
and respiratory effects have not been reported following intravenous methadone 20 mg, also given as a bolus over 1 min. in patients under general anesthesia [ll--13,15.38]. Therefore, it is unlikely that large quantities of methadone entered the brain-stem solely by distribution through the peripheral circulation. Supraspinal transport may. however, occur by an intravascular route which is more direct than the caval venous system. Consequently. the rapid transport of methadone upto the vital centers may result from passage into vascular channels which connect directly with supraspinal areas [5.41]. Although blood opioid levels are usually insufficient to induce systemic analgesia [8,39]. they may be responsible for the generalized side effects, i.e., pruritus, drowsiness. vomiting, and respiratory depression [24]. In conclusion, it is possible to obtain prolonged postoperative analgesia following intrathecal morphine but not methadone. Lipid solubility is an important determinant of duration of effect of intrathecal opioids. A CSF reservoir of opioid is best obtained by using lipid insoluble agents such as morphine.
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Pain, 43 (1990) 141-148 Elsevier
PAIN 01671
Clinical Section Intrathecal methadone: a dose-response study and comparison with intrathecal morphine 0.5 mg * Louis
Jacobson,
Department
Charles
Chabal,
Michael
C. Brody
a, Richard
J. Ward
and
Loretta
Wasse
of Anesthesiology, University of Washington School of Medicine, and VA Medical Center, Seattle, WA 98108 (U.S.A.). and o Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15213 (U .%A.) (Received
20 December
1989, revision received and accepted
31 May 1990)
Summary
The analgesic and adverse effects of intrathecal methadone 5 mg, 10 mg and 20 mg were assessed and compared with intrathecal morphine 0.5 mg. The study was conducted on 38 patients who underwent total knee or hip replacement surgery. The intrathecal opioid was administered at the end of surgery and assessments began 1 h thereafter and continued for 24 h. Pain measurements, supplementary analgesia requirements, and adverse effects were recorded. Intrathecal morphine 0.5 mg provided effective and prolonged analgesia. Intrathecal methadone 5 mg, 10 mg, and 20 mg produced good analgesia of 4 h duration. Thereafter the median pain scores with intrathecal methadone were consistently higher (worse) than those with intrathecal morphine (P < 0.05). The time to the onset of discomfort severe enough to require supplemental morphine was longer after intrathecal morphine than following methadone (15 h with morphine 0.5 mg; 6.25 h, 6.5 h and 6 h with methadone 5 mg, 10 mg, and 20 mg respectively: P < 0.05). Central nervous system depression manifesting as respiratory depression, hypotension, and excessive drowsiness occurred in 3 of 8 patients injected with methadone 20 mg intrathecally. Generalized pruritus, nausea, vomiting, and urinary retention were common and equally distributed among the treatment groups. We conclude that both intrathecal morphine 0.5 mg and methadone 5, 10, and 20 mg provide excellent analgesia but that morphine has a more prolonged effect. Methadone 20 mg produced unacceptable side effects. Clinical evidence for rostra1 spread of methadone within the CSF, as indicated by facial itching and excessive drowsiness, was less apparent with 5 mg than with 10 and 20 mg. Various explanations for the observed differences between the drugs are discussed. Key words Analgesia,
postoperative;
Opiates,
methadone,
morphine;
Introduction An alternative intrathecal opioid to morphine is desirable because intrathecal morphine is associated with a high incidence of side effects such as pruritus, nausea, vomiting and urinary retention
* Work performed
at the Seattle VA Medical
Center.
Correspondence to: Louis Jacobson, M.D., Anesthesiology Service (112A), VA Medical Center, 1660 South Columbian Way, Seattle, WA 98108, U.S.A.
03043959/90/%03.50
0 1990 Elsevier Science Publishers
Anesthetic
techniques,
spinal;
Opiates,
intrathecal
[18]. Sustained respiratory depression can also occur with intrathecal morphine administration [18]. A satisfactory alternative should provide profound and prolonged analgesia without adverse effects. Methadone is a lipophilic opioid which is rapidly cleared from the cerebrospinal fluid (CSF) [32]. With doses of 2-5 mg, little if any is available to brain-stem opioid receptors [25,32]. Therefore, intrathecal methadone could produce analgesia by a predominantly spinal mechanism, resulting in fewer supraspinal adverse effects than with intrathecal morphine. Intrathecal methadone 1 mg, however, provides inferior postoperative analgesia
B.V. (Biomedical
Division)
to morphine 0.5 mg and 1 mg which produce profound and prolonged analgesia [ 191. Methadone possesses physicochemical properties which confer on it the ability to provide prolonged analgesia when given intravenously in large doses of 20 mg or greater [ll 13.15,39]. Sufficient quantities of methadone injected intrathecally might also be capable of producing prolonged analgesia. Therefore, in order to determine whether larger doses of methadone could provide satisfactory, safe and prolonged postoperative analgesia, we compared intrathecal methadone 5 mg, 10 mg and 20 mg with intrathecal morphine 0.5 mg, an effective and safe dose [18.19].
Methods The project was approved by our Human Subjects Review Board and the Federal Drug Administration (FDA). Written informed consent was obtained from each patient preoperatively. Subjects for the study were 38 men scheduled for total knee or hip replacement surgery. Relevant patient data are outlined in Table I. The study was conducted in 3 consecutive stages. Initially the subjects were divided into 2 groups: (1) intrathecal morphine 0.5 mg (n = lo), and (2) intrathecal methadone 5 mg (n = 10). The patients were randomly assigned to a treatment group and the drug was administered, over approximately 1 min, in a double-blind manner. Commercially available preservative-free morphine (Duramorph) 1 mg/ml and methadone (Dolophine) 10 mg/ml were used, and all injectates were standardized to a volume of 1 ml with sterile water. Stage 2 involved the administration of intrathecal methadone 10 mg (1 ml) to 10 consecutive patients under single-blinded (to the patient) and controlled conditions. In the final phase (stage 3). methadone 20 mg (2 ml) was injected intrathetally to 8 patients under identical conditions to stage 2. The study was terminated after adverse effects occurred in 3 of 8 subjects who received intrathecal methadone 20 mg. No premeditation, intraoperative opioids or long acting sedatives were given. Except for these constraints the type of anesthesia was at the
anesthesiologist’s discretion and involved inhala tional general anesthesia (21 patients), lumbar epidural anesthesia (5 patients) and subarachnoid anesthesia (12 patients: see Table I). The average duration of surgery was 3.5 h. The intrathecal opioid was injected at the end of the surgical procedure. Systemic opioids were withheld until requested or recommended in the postoperative period, when incremental small doses of intravenous morphine were given until satisfactory analgesia (nil or mild discomfort) was obtained. Subsequently, morphine was administered intramuscularly according to the patients’ requirements. The time at which initial discomfort occurred was recorded. as were the times when supplementary morphine analgesia was given. Assessments during stage 1 (morphine 0.5 mg versus methadone 5 mg) were conducted by an investigator who was unaware of the constituents of the subarachnoid injection. Thereafter, fat methadone 10 mg and 20 mg, the assessor knew the injectate contents. The assessments commenced 1 h after the injection and continued for 24 h. Observations were conducted at hourly intervals for the first 6 h after the opioid injection. Further assessments were done at 8 h, 18 h and 24 h post injection. Pain was assessed by verbal patient response using a numerical pain rating system (0 = no pain to 10 = worst pain imaginable) [6,20]. Adverse effects monitored included pruritus. nausea, vomiting. excessive sedation, respiratory depression and urinary retention requiring catheterization. Assessments of sedation and respiration were done with the subjects at rest and undisturbed prior to making the remaining observations. Sedation was assessed using a rank scale A to D where A = awake and alert; B = dozing and easily roused; C = dozing and roused with difficulty; and D = unrousable/unresponsive. Patients in categories C and D were considered to be excessively sedated. Ventilation was gauged with repeated measurements of arterial blood gas tensions performed with the subjects undisturbed at each assessment interval upto and including 8 h. All the patients had indwelling arterial cannulae from which blood samples were easily and painlessly withdrawn. Statistical analysis of differences in times until
143
supplementary morphine was needed and the numerical pain scores were accomplished using the Kruskal-Wallis analysis of variance by ranks [lo]. Qualitative data were analyzed by the Fisher Exact Probability test. A probability of less than 0.05 (P < 0.05) was considered statistically significant.
TABLE
II
MEDIAN
PAIN SCORE
Data are median Time (h) after opioid injection
Results
2
There were no significant differences between the groups in age, weight or height (Table I). The operative procedures and anesthetic techniques were equally represented in the different age groups (Table I). Both intrathecal morphine and methadone provided excellent analgesia for the first 4 h post injection (P -c 0.05). Thereafter, the median pain scores with intrathecal morphine were consistently lower than those with intrathecal methadone 5 mg, 10 mg and 20 mg (P > 0.05; Table II). The time to onset of discomfort severe enough to require supplemental morphine was longer with intrathecal morphine than intrathecal methadone TABLE
I
CLINICAL Data
DATA
are median
with interquartile Dose of intrathecal
Methadone
0.5
5
10
Height
(cm)
Surgical Hip
opioid (mg)
Morphine
n Age (years) Weight (kg)
range in parentheses.
(59-72) 66 86 (80-115) 175 (170-184)
procedures
10 10
(61-71) 65 87 (68-95) 176 (169-187)
20
10 (42-74) 65 83 (744100) 182 (1788185)
8 (::-73) 75 (54-85) 172 (170-175)
4
6
3
replacement
5
6
4
5
General Spinal Epidural
4 5 6 8
(no. of patients) 6 5 3 3 1 2
5 3 2
5 3 0
O-10)
opioid (mg)
Methadone 5 0
(o-0.25) 0
10
20
0 _
0 _
0
0 _
(O-2)
(O-2) 0 (O-0.5) 0
(O-l) 0 (O-3)
1 (O-5.5) 1
(O-l) 0 (O-0.75) 0 (O-0.75) 0 (O-0.5)
(O-6.5) 3 (l-5.5) 4 (l-5.5) 3.5
(O-7) 2.5 (O-6.5) 3 (0.5-6) 5.5
(O-4) 1.5
(l-5)
(2-7)
(O-5)
0 _
0.5
(O-5) 4.5 (O-6) 3
(P < 0.05; Table III). The median time to initial supplementation analgesia was 15 h with morphine 0.5 mg, and 6.25 h, 6.5 h and 6 h following intrathecal methadone 5 mg, 10 mg and 20 mg respectively. The total amount of supplementary morphine needed in the 24 h following the subarachnoid injection was significantly less in patients receiving morphine than methadone intrathecally (P < 0.05; Table III). On average 5.5 mg of supplemental morphine was needed following intrathecal morphine 0.5 mg as compared to 23 mg, 22 mg
TABLE
III
ANALGESIA:
NEED
Data are median
FOR SUPPLEMENTAL
with interquartile
Time to first analgesia (h) Amount of suppl. morphine in 1st 24 h (mg)
opioid (mg)
Morphine
Methadone
0.5
5
10 6.25
(::_27) 5.5 (O-24)
OPIOIDS
range in parentheses.
Dose of intrathecal
5
technique
Morphine ~ 0.5
(no. of patients)
replacement Knee
Anesthetic
3
SCALE
range in parentheses.
Dose of intrathecal
0.5 (O-2.5) 0.5
1
(VERBAL
with interquartile
(4-9) 23 (9-33)
6.5 (5-10) (Z-50)
20 6 (4-10) $45)
144
and 30 mg for intrathecal methadone 5 mg, 10 mg and 20 mg respectively. Respiratory depression (p,CO, > 50 mm Hg) occurred only with intrathecal methadone 20 mg (P < 0.05; Table IV). The median paC02 levels with methadone 20 mg were consistently elevated from 1 to 3 h post injection (P < 0.05; Fig. 1). These data do not include values following naloxone therapy. The median paCOz remained within normal limits after methadone 5 mg and 10 mg as well as morphine 0.5 mg. Pruritus was frequently encountered in each group (P > 0.05; Table IV). Following methadone the itch was apparent by 1 h post injection and had usually receded at 4 h or shortly thereafter. lntrathecal morphine was associated with itching of slower onset and longer duration. The pruritus was minor and required no treatment. Urinary retention, nausea and vomiting were common in all the treatment groups (P > 0.05;Table IV). There was no evidence of motor or sensory impairment associated with either intrathecal morphine or methadone. There was a tendency for excessive drowsiness (levels C and D) to manifest more commonly in the methadone 10 mg and 20 mg groups (Table IV). This was, however, only a trend and was not statistically significant (P > 0.05).
TABLE
IV
ADVERSE
EFFECTS
Data are the number of patients manifesting the adverse effect (numerator) and the total number (denominator). Those patients with elective preoperative urinary bladder catheterization were excluded. Dose of intrathecal Morphine
Pruritus Facial pruritus Nausea/vomiting Resp. depression (p,CO, > 50 mm Hg) Excessive drowsiness Urinary retention requiring catheterization
opioid (mg)
Methadone
0.5
5
10
20
6/10 6/10 6/10
6/10 O/IO l/10
8/10 5/10 3/10
5/8 5/x 4/8
O/10 o/10
O/10 l/10
O/10 4/10
4/8 3/8
6/7
5/9
6/8
5/l
““;
6
Time (hours) after intrathecal
8 injection
Fig. 1. The effect of intrathecal methadone and morphine on paCO,. Data are median p,CO, with quartile deviation represented by the bars.
Central nervous system depression comprising hypotension, respiratory depression and excessive sedation (levels C and D) occurred in 3 of 8 patients who received intrathecal methadone 20 mg. This appeared 5-10 rnin post injection with excessive drowsiness and hypotension. All 3 patients were clinically normovolemic and maintained a constant heart rate throughout the episode. Phenylephrine infusion rapidly restored and maintained the blood pressure. Apnea supervened in the 3 patients at 10 min, 30 min and 45 min respectively. A single dose of naloxone (SO- 120 pg) administered in 40 pg aliquots permanently restored clinically satisfactory spontaneous ventilation without reversal of analgesia.
Discussion
Intrathecal methadone was as potent trathecal morphine thereby confirming the data which suggests that 8.5 mg methadone provide analgesia equivalent to morphine [26]. Information obtained from intrathecal
as inanimal should 0.5 mg meth-
145
adone 1 mg [19] as well as the 5 mg, 10 mg, and 20 mg, used in this study, indicate that the minimal effective dose of intrathecal methadone lies between 1 mg and 5 mg. Although clinical potency did not differ between methadone and morphine, duration of action did. There were big differences in the duration of analgesia and the amount of supplemental morphine required between the morphine group and all the methadone groups. Intrathecal morphine reliably produced profound and prolonged analgesia, whereas intrathecal methadone was of shorter duration. Intrathecal methadone 20 mg provided neither the prolonged analgesia attributable to intrathecal morphine [5,18,19,31] nor the extended analgesia associated with the same dose of intravenous methadone (20 mg) [ll-13,151. Lipid solubility is an important determinant of CSF elimination and duration of action of opioids administered intrathecally. A CSF reservoir of opioid is important in maintaining an adequate concentration gradient to the spinal opioid receptors. Morphine is the least lipophilic of the clinically used opioids. Following lumbar intrathecal administration, a highly ionized and hydrophilic drug such as morphine remains in the CSF and results in high and sustained CSF morphine concentrations [21,22,28, 31,371. High blood concentrations are not associated with intrathecal morphine therapy [4]. Intrathecal methadone is rapidly cleared from the CSF [25,32] and there is no reservoir for maintaining CNS concentration over prolonged periods. Large doses of lipophilic opioids injected intrathetally are rapidly absorbed into the plasma [24,29] but the ensuing blood levels are usually insufficient to induce systemic analgesia [8,24,39]. Intrathecal methadone may enter the circulation at a lower rate than the systemic clearance rate. Consequently, intrathecal methadone probably reached the circulation in insufficient quantities to manifest prolonged analgesia. The fat-rich areas of the CNS possibly acted as a reservoir for large amounts of methadone which attached to opioid receptors and/or were sequestered in the lipid layers by non-specific binding [26,40]. The CNS storage of methadone might have constituted a slow release mechanism for methadone to access the circulation in subanalgesic concentrations.
Morphine and methadone are both mu opioid receptor agonists which have similar, relatively high, affinity for the mu receptor and little for the other opioid receptors [26]. Consequently, it is unlikely that potentially confounding variables such as mu receptor affinity and affinities for different opioid receptor subtypes played a clinically significant role. Other factors such as rate of metabolism, molecular size, and molecular shape also probably exerted little influence [27]. However, there is no clinical evidence to support these contentions and it should be acknowledged that morphine and morphine-6glucuronide have some affinity for delta receptors. Limitations of the study should be acknowledged. Its conditions precluded the assessment of the onset of analgesia. Another shortcoming was that the study was not simultaneously doubleblinded for all the doses of intrathecal methadone. Methadone 20 mg (10 mg/ml) is a 2 ml solution. All the preceding drugs and doses were administered in a 1 ml volume. It is conceivable that the volume of the 20 mg injectate contributed to the predilection for rostra1 supraspinal effects. However, previous studies with intrathecal morphine 0.3, 1 and 2.5 mg all administered in 2.5 ml showed that the dose and not the volume (2.5 ml) was important in producing adverse supraspinal effects [18]. Therefore, it is likely that the supraspinal effects of methadone 20 mg in 2 ml were mainly the result of the dose and not the volume of the injectate. The FDA, the Human Subjects Review Board, and common sense dictated that we proceed cautiously because of the limited use of intrathecal methadone in both animals [32] and humans [19,25]. Each preceding dose had proven safe and comparable large doses of intrathecal meperidine [9,24,29] and intrathecal morphine [4,34,35] had been safely administered to humans. Central nervous system depression comprising hypotension, drowsiness, and respiratory depression occurred in 3 of 8 patients following intrathecal methadone 20 mg. Spinally administered opioids may exert physiological actions on the cardiovascular system that are not observed at concentrations reached by systemic doses [42]. Opioid peptides and opiate receptors have been
146
localized in brain structures involved in the central regulation of hemodynamic as well as respiratory functions [1,2,7,36]. Hypotension and bradycardia have been observed following opioid injection into the cisterna magna or fourth ventricle of animals [3,23]. The hemodynamic effects of intrathecal methadone 20 mg may be due to its action on central cardiovascular regulation centers. The most plausible explanation for the rapid and profound CNS depression associated with intrathecal methadone 20 mg is direct depression of the cardio-respiratory areas in the brain-stem by large concentrations of methadone which migrated rostrally within the CSF. Evidence is available for minimal vascular uptake, rapid dural transfer into CSF and rapid rostra1 movement in the CSF of lipid-soluble opioids administered epidurally [16,17]. The average time to the maximum cervical CSF fentanyl concentration following lumbar epidural administration was 22.5 min, but in 2 patients peak levels were reached 10 min after irrjection [77]. Epidural fentanyl 200 pg inhibits ventilation from 30 to 120 min post injection probably as a consequence of cephalad migration of fentanyl in CSF [30]. These observations correlate with the pattern of supraspinal adverse effects noted with methadone 20 mg in this study. Furthermore, rapid unpredictable cephalad spread of spinal local anesthetics occurs regularly in routine clinical practice, and total spinal anesthesia manifesting within 10 n-tin of injection of 15 mg of spinal bupivacaine has been reported (331. It is therefore apparent that opioids and local anesthetics injected in the lumbar intrathecal space can rapidly reach supraspinal areas of the CNS as a result of passive CSF flow, thereby providing circumstantial evidence to support our explanation of the adverse effects of intrathecal methadone 20 mg. Lipophilic opioids injected intrathecally are absorbed into plasma [22,24,28,37]. Measurable amounts of methadone, morphine, and meperidine rapidly appear in the blood following high dose intrathecal administration [4.24,25,29]. Consequently rapid intravascular uptake and supraspinal distribution via the blood may be involved in the transport of large quantities of methadone to the brain-stem. However, similar cardiovascular
and respiratory effects have not been reported following intravenous methadone 20 mg, also given as a bolus over 1 min. in patients under general anesthesia [ll--13,15.38]. Therefore, it is unlikely that large quantities of methadone entered the brain-stem solely by distribution through the peripheral circulation. Supraspinal transport may. however, occur by an intravascular route which is more direct than the caval venous system. Consequently. the rapid transport of methadone upto the vital centers may result from passage into vascular channels which connect directly with supraspinal areas [5.41]. Although blood opioid levels are usually insufficient to induce systemic analgesia [8,39]. they may be responsible for the generalized side effects, i.e., pruritus, drowsiness. vomiting, and respiratory depression [24]. In conclusion, it is possible to obtain prolonged postoperative analgesia following intrathecal morphine but not methadone. Lipid solubility is an important determinant of duration of effect of intrathecal opioids. A CSF reservoir of opioid is best obtained by using lipid insoluble agents such as morphine.
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