- Email: [email protected]
Cocaine and morphine interaction in acute and chronic cancer pain
35
Pain, 31 (1987) 35-45 Elsevier PA1 01113
Cocaine and ~o~hine interaction in acute and chronic cancer pain 1 Robert F. Kaiko ‘, Ronald Kanner b, Kathleen M. Foley ‘vd, Stanley L. Wallenstein ‘, Anne Marie Cane1 ‘, Ada G. Rogers ’ and Raymond W. Houde ’ Frederick Co., Norwalk, CT (U.S.A.), ‘Albert Einstein College of Medicine, Bronx, NY (U.S.A.), ‘Analgesic Studies Section and Pain Service, Memorial Sloan-Kettering Cancer Center, New York, NY (U.S.A.), and d Cornell University Medicul College, New York, NY (U.S.A.)
’ Purdue
(Received 17 December 1986, revised received and accepted 14 April 1987)
An evaluation of the analgesic, mood and side effects of the combination of intramuscular morphine and oral cocaine was conducted in 17 patients with postoperative pain and 19 others with chronic malignant pain for the purpose of assessing the therapeutic merits of so-called ‘euphoriant’ elixirs in the management of pain in cancer patients. The study was designed as a randomized and double-blind single dose but complete cross-over comparison of the combination of 10 mg intramuscular morphine and 10 mg oral cocaine with morphine alone, cocaine alone, and placebo. While patients clearly discriminated between the analgesic effects of morphine and placebo, there were no differences in the analgesic responses to cocaine and placebo, or in responses to morphine and the combination of morphine and cocaine in either patient group. Side effects were predo~n~tly mo~hine-like and occurred in 59% of patients after the combination, 43% after morphine, 34% after cocaine and 25% after placebo. interaction effects between cocaine and morphine were observed in terms of positive changes toward selected aspects of mood (e.g., cheerful, friendly) in postoperative patients but toward negative aspects of mood (e.g., sad, serious) in patients with chronic pain.
S-arY
Key words: Analgesics; Cancer pain; Postoperative pain
i Supported by USPHS Grants DA-01707, CA-32897 and CA-08748. Previously presented, in part, at the Fourth World Congress on Pain of the International Association for the Study of Pain, Seattle, WA, August 31-September 5, 1984, and at the Forty-Seventh Annual Scientific Meeting of The Committee on Problems of Drug Dependence, Inc., Baltimore, MD, June to-12,1985. Correspondence to: Dr. Kathleen M. Foley, Memorial Sloan-Kettering Avenue, New York, NY 10021, U.S.A.
Cancer Center, 1275 York
0304-3959/87/$03.50 0 1987 Elsevier Science Publishers B.V. (Biomedical Division)
Following successful use of the Brompton’s cocktail in the i~lat~agenlent of chronic malignant pain [lO,ll]. we began a series of studies designed to evaluate the components of this oral (p.0.) mixture for their therapeutic merits. The cocktail, as once employed at St. Christopher’s Hospice in London, contained a mixture of heroin, cocaine, ethyl alcohol, and a phenothiazine. Our studies of heroin following single intramuscular (i.m.) administration in cancer patients with postoperative or chronic malignant pain revealed it to have no unique advantages over currently available analgesics [6,7]. Additional pharmac~~ki~~etic f3] and opiate receptor hinding studies [4] indicate that heroin’s actions are mediated primarily by active metabolites, monoacetylmorphine and morphine. Today, the so-called ‘euphoriant’ elixirs usually consist of aqueous solutions of morphine. alone [14]. This is due. in part, to evidence that the presence of cocaine provides no significant therapeutic advantage in the management of chronic malignant pain 19.121. Both these latter studies, however, lacked an internal control. or intrinsic measure of assay sensitivity. a basic requirement of a meaningful and ~eII-c~)ntrolled study [13J. Definitive conclusions cannot he drawn when ‘no differences’ occur in the absence of an internal control. Intranasal cocaine can, in fact, decrease experimentally induced pain [16] and i.m. dextroamphetamine, another sympathomimetic agent, can double the analgesic potency of morphine in postoperative pain [l]. The objective of the present study was to assess the analgesic efficacy of cocaine in the dose most commonly used in Brompton’s cocktail, and to assess its interaction with morphine in terms of analgesia and other effects in cancer patients with p~~st~~perative and chronic malignant pain.
Methods The study was designed as a randomized, double-blind, single dose, complete cross-over, factorial assay incorporating 4 study medications: placebo, 10 mg p.o. cocaine, 10 mg i.m. mo~hine, and cocaine plus morphine. Procedures and assessment instruments have been previously described in detail [2,6,13]. Briefly, study medications were administered for moderate or severe pain at least 3 h after any prior analgesic, and assessments were obtained at baseline and at 30 and 60 min and hourly thereafter until pain returned to baseline but for no longer than 6 h. Pain intensity and relief were assessed using both categorical and visual analog scales (VAS). Global mood was assessed using a VAS and selected aspects of mood were assessed using a questionnaire consisting of 15 contrasting word/phrase pairs. This latter questionnaire was ad~nistered at baseline and 2 h only in order to limit the stress of questioning on weak and debilitated patients. Spontaneously reported and/or observed side effects were recorded. The study protocol was approved by the Memorial Hospital Institutional Review Board, and all patients who participated in the study gave their written, informed consent. Patients’ reports on their pain, mood, and the occurrence of observed or
31
TABLE
I
PATIENT CHARACTERISTICS AND BASELINE ATIVE AND CHRONIC PAIN STUDY PATIENTS
PAIN
CHARACTERISTICS
Postoperative
Chronic
Males (N) Females (N)
16 1
8 11
Mean age (range)
43 (22-65)
53 (34-67)
61 39
45 55
56 20 11
21 22 16 17 23 2
FOR
POSTOPER-
Baseline pain * Intensity (%) Severe Moderate Site (%) Chest Back Pelvis Abdomen Extremities Head and neck
4 9
Character (%a) Sharp Dull Tight Pulling Throbbing Soreness Crampy Radiating Burning * Incidence
of pre-study
57 33 2 4
26 40 12 15 7 7 2 2
2 2 medication
baseline
pain characteristics
reported
as percent.
reported side effects were obtained by trained .registered nurse observers before the patients received the test medications and at the prescribed intervals thereafter. The demographic and baseline pain characteristics of the patients are summarized in Table I. Thirty-six patients entered the study and 20 completed all data for the 4-way cross-over. Nine postoperative and 11 chronic patients provided these complete data. 17 postoperative and 19 chronic pain patients received a total of 54 and 58 study medications, respectively. The following pain and patient characteristics are based on all patients. Postoperative patients averaged 43 years of age (range, 22-65) and chronic patients, 53 years (range, 34-67). There were disproportionately more men among postoperative (16 men and 1 woman) than among chronic (8 men and 11 women) patients. Patients were receiving a routinely ad~nistered analgesic (e.g., hydromo~hone, oxycodone, morphine or meperidine, most commonly in both groups) prior to and between study medications. The majority of postoperative
patients had thoracotomies and incisional pain in the chest (56%). Pain site was more diverse (e.g., chest, back, abdomen, arms) among chronic patients. Postoperative patients described their pain as sharp in most cases, while chronic patients usually most commonly described their pain as dull, aching and diffuse. Concordantly, postoperative patients categorized their pain as ‘severe‘ more frequently (61%) than chronic patients (45%). In contrast. postoperative patients reported more positive scores than chronic patients on several selected aspects of mood (e.g., pessimistic/optimistic, shaky/serene, angry/friendly, apprehensive/confident. sad/happy and nervous/calm ).
Results Fig. 1 shows time-effect curves in terms of VAS scores for pain intensity, and mood for the 9 postoperative and 11 chronic patients completing
Poetopera~ive Pain
pain the
Chronic Pain
30 OTT----i-
6/O
2
4
6
Hours T’ime-course of pain intensity, pain relief and mood foIIo~ng placebo, morphine, cocaine and the combmation in 9 postoperative and 11 chronic cancer patients with pain. Each point represents the mean visual analog scale score on a 100 mm scale. Solid symbols represent study medications containing morphine. and dashed lines represent study medications containing cocaine. A- - - - -A, morphinetplacebo. cocaine: A ----A*, morphine alone; a- - - - - -A, cocaine alone; A ------A,
39 TABLEII ANALGESICAND MOOD VISUALANALOG SCALES(millimeters)FOLLOWINGPLACEBO, MORPHINE,COCAINEANDTHEIR COMBINATIONIN 9 POSTOPERATIVE AND 11CHRONIC PATIENTS TOTPAR,total pain relief as measured by the area under the pain relief time-effect curve; PID, pain intensity difference (change in pain as compared to pre-treatment intensity differences. Placebo
Morphine
pain level); SPID, sum of pain
Cocaine
Combination
Peak pain relief Postop. Chronic
53 34
63 68
44 39
69 58
TOTPAR Postop. Chronic
90 87
135 193
70 76
161 176
Peak PID Postop. Chronic
31 13
51 42
26 25
51 35
SPID Postop. Chronic
58 22
99 109
35 45
10s 90
Peak change mood Postop. Chronic
14 12
33 23
6 24
28 -11
17 8
-6 11
14 4
Mean change Postop. Chronic
mood
-5 3
4-way cross-over and providing complete data. Morphine, alone, provided greater effects than placebo in terms of all 3 effect measures in both patient groups, while cocaine, alone, was not significantly better than placebo in terms of pain intensity and relief. Higher, but not significantly different, mood scores were observed after cocaine than after placebo in the postoperative patients. The combination of morphine and cocaine was comparable to morphine, alone, for both estimates of analgesia in all patients. Again, higher, but not significantly different mood scores followed the cocaine-containing treatment in the postoperative patients. Table II lists the summary VAS data for peak pain relief, total pain relief (TOTPAR), peak and total pain decrease (Peak PID and SPID), and mood change following each study medication. Analgesic and mood effects of these data were analyzed according to the paradigm in Table III, showing the orthogonal comparisons for the factorial assessment of drug and interaction effects in the two-way analysis of variance. The morphine effect was assessed by ~ompa~son of the two mo~~ne-contai~ng treatments to the treatments not containing morphine. The cocaine effect was assessed similarly. The interaction effect was assessed by com-
40 TABLE
III
~RTHO~~AL FACTORIAL CO~PARIS(~NS EFFECTS DERIVED FROM DA-I-A IN TABLE
OF MAIN Ii
TRE,~TM~NT
AND
iN-r~RA~“rlON
TOTPAR, total pain relief as measured by the area under the pam relief time-effect curt’e: PlD, pain intensity difference (change in pain as compared to pretreatment level): SPID. sum of pain intensit) differences.
~__. Treatments
Morphine
Placebo Morphine Cocaine Combination
I. +
Peak pain relief Postop. Chronic TOTPAR Postop. Chronic Peak PID Postop. Chronic
----__ Effects * cocaine
----_ Interaction
-I-
t t .. 3
35 53(P
135 (f < 0.025) 206 (P < 0.05)
39(PiO.O1) 39 (P i 0.005)
SPID Postop. Chronic
+
5
IS
-15
6 _ 28
46 ._6
11 5
11 - 19
‘- 14 4
32 .- 42
3 -46(P
-’
Peak change mood Postop. Chronic
41 ( P c 0.005) -24
- 13 -34
Mean change mood Postop. Chronic
42 (P < 0.005) -2
4 4
7
-12
* Derived factorial effect vaiues are obtained by summing or subtracting the appropriate means in Table II according to the designated signs in the 3 coIumns above. * Probability values of 0.05 or less are shown in parentheses.
treatment
parison of the morphine/cocaine combination plus placebo to morphine, alone, plus, cocaine, alone. Significant effects on al1 analgesic measures were observed for morphine in both postoperative and chronic pain patients. In contrast, the morphine mood effect was significant only in postoperative patients, and a significant negative peak mood interaction effect was observed only in chronic pain patients. Fig. 2 illustrates the word/phrase pair data from each of the study medications. These data represent mean 2 h minus baseline changes in mood score. The pairs are arranged in descending order of the morphine effect. Generally, morphine produced positive changes, with the exception of a significant change toward ‘apathetic’
41
-1
PUCE60 n +I
F.--+-T
Sad I Happy
+I 0
Shaky i Serene
0
Restless I Peaceful Nervous
I Calm
Uneasy I At ease Blue/Cheerful
3
‘I--
I 0
3 o-+--_ --*
Alone I Sociable
*___-
Apprehensive
ea---
Angry f Friendly Pessimistic
I Optimislic
Heavy I Buoyant Lethargic Apathetic
I Peppy / Enthusiastic *_
-1
I
1
I
COCAINE 0 +l ,
,
COMBINATION -1 0 +I r----m
--b * -* ______+*
I Interested +------‘@ /Amused +I Confident
MORPHINE 0 +1
0
-_,
Uninterested Serious
-1
--0 0
~
*
+-
Q-
+-
I
rs__%
Fig. 2. Zero to 2 h change in contrasting mood word phrase pairs following placebo, morphine, cocaine and the combination in cancer patients with postoperative pain and with chronic pain. Solid symbols and lines represent data from patients with postoperative pain and open symbols and dashed lines represent data from patients with chronic malignant pain. Each point represents the mean difference between the 2 and 0 h scores and is plotted toward the right of the vertical ‘baseline’ if the mean score is positive and toward the left if negative. Asterisks indicate statisticatly significant (P c 0.05, paired two-tailed f test) changes.
feelings among chronic pain patients. Cocaine provided generally positive mood changes in chronic pain, with significance achieved in terms of ‘happy’ and ‘buoyant.’ In contrast, cocaine provided generally negative changes in postoperative pain, with significance achieved in terms of ‘alone.’ The combination of morphine and cocaine provided generally positive mood changes, especially in postoperative pain. On the other hand, as with cocaine alone, placebo appears to have differential mood effects in postoperative pain in comparison to chronic pain. Worsening mood in chronic pain following placebo contrasts with the opposite trends following cocaine. Differential mood effects were examined by factorial analyses of variance of the data from the &item mood questionn~re. The analysis is similar to that carried out on the VAS data in Table III. Fig. 3 shows calculated results. The word/phrase pairs are arranged with the negative aspect on the left and in descending order of the morphine effects. As with the VAS mood data, use of the U-item mood questionnaire resulted in generally positive morphine mood effects but achieved statistical significance in postoperative patients only, while there was a trend toward more positive cocaine effects in chronics than in postoperative patients. Most striking differences were apparent in the consistent differential direction of interaction mood effects. Significant positive interaction effects were observed in postoperative patients in terms of being more ‘cheerful’ and ‘friendly.’ Significant negative
1V
(SE) FOLLOWING PAIN PATIENTS
4 16 4 2s 8
13 6 46 27
12 2 17 2
2 1 1
7
8 3 3
6
M C ~-__-_~-.._._~____I-.~_ 13 16 _
pain
(P). MORPHINE
I
1
12 -I
P
Postoperative
Medication
PLACEBO (PTS)
16 5 31 7
2 2 13 I 54 14
3
1 1 2
4 2 2
16 _
13 _
Chronic
pain
13 6 46 9
3 1
1
14 9 64 20
8
8 1
I~-- 14
MC
_-.___._____ .-_
__~
5
15 6 40 22
_.
C 13
-. . ._-. . .
___
IN POSTOPERATIVE
_. ---- ___--
1 2
-
-__-
-_..
(MC)
4 3 2 4 1 8
15 _
M
--~-___
COMBINATION
-.-----..-
THEIR
P
-
(c’) AND
MC
(M). C‘OCAlNE
* Sedative (sleepy. relaxed. groggy, weak). mental clouding (lightheaded. floating feeling. difficulty concentrating. unable to focu\ .tt!ention. space). disoriented, hazy feeling, feeling of unreality), cardiovascuIar/histammic (sweating, warm feeling, tachycardia. hot. itching). emetic (nausea. vomiting). excitatory (nervous, tense. excited. hypertemion). and other (dry mouth, mlection pam. angry, headache. dyspepsia. dizzy. hiccough>. hungry. difficult> speaking, cold) are listed in terms of the number of occurrences and/or observed.
NPTS N PTS with SE % with SE Total N of SE
Sedative Mental clouding Cardiovascular/histaminic Emetic Excitatory Other
N SE *
_
SIDE EFFECTS AND CHRONIC
TABLE
43
-1
i-
Sad f Happy Blue f Cheerful Uneasy I At ease Alone I Sociable
MORPHINE n
COCAINE 41
-1
d c
rl
Cl
-1
INTERACTION 0 +l
/
,
I
0 Q___-_ d
Q Q__-__ +Q-
Nervous/Calm Uninterested I Interested Shaky I Serene
Q-Q___
Apprehensive I Confident
a--
Restless I Peaceful
c--
Apathetic I Enthusiastic Angry / ~riendiy Lethargic / Peppy Serious / Amused Heavy I Buoyant Pessimistic I Optimistic
---0 4--
c
QCQ______ 0
i+
Fig. 3. Factorial morphine, cocaine and interaction effects in terms of contrasting mood word phrase pair O-2 h changes in cancer patients with postoperative pain and with chronic pain. Solid symbols and lines represent data from patients with postoperative pain and open symbols and dashed lines represent data from patients with chronic malignant pain. Each point represents the mean effect and is plotted toward the right of the vertical line if the mean effect is positive and toward the left if negative. Superscript letters indicate level of statistical significance (P < 0.05 for a, 0.025 for b, 0.01 for c, 0.005 for d, 0.001 for e) from two-way analyses of variance for factorial design with 1 and 35 degrees of freedom. See Table III for procedure for calculating the orthogonal comparisons for morphine, cocaine and interaction effects.
interaction
effects were observed in chronics in terms of being more ‘sad,’ ‘blue’ and “serious.’ Taken together, these two series of analyses demonstrate that the differential interaction effects are related, in part, to differential effects of placebo and cocaine in postoperative and chronic pain, as is graphically indicated by the directions of the arrows for the various mood items in Fig. 2. Table IV shows side effect data for both postoperative and chronic pain patients. The effects were typically morphine-like in most cases. The combination of drugs produced the highest occurrences (percentage of patients with side effects) and both morphine and cocaine, alone, produced higher occurrences than placebo in both patient groups. While the addition of cocaine to morphine was associated with a decrease in the total number of side effects in postoperative patients, the percentage of postoperative patients with side effects was actually higher following the combination. This was related to one patient who reported a large number of ‘mental clouding’ effects following morphine, alone.
Discussion
The dose of cocaine most commonly used in the Brompton’s cocktail had no analgesic effect of its own, nor did it alter the morphine analgesia. These results are
44
consistent with those of other investigators who found no differences tn analgesi:l with the addition of 10 mg p.o. cocaine to morphine or heroin in the m;magetnent or chronic malignant pain [9,12]. Omission of an internal measure of assay sensitivit> from these latter studies, however, made us question whether or not those studies were sufficiently sensitive to detect clinicall> significant differencex. The ;Ibility (if patients to discriminate clearly between the analgesic effects of tnt~rphit~e ‘and placebo provided a measure of sensitivity in the current study. It is not unfikel! that. at higher doses. cocaine could increabe the effectiveness of morphine in 3 similar manner as dextroamphetamine [ 1J. Cocaine, alone, had negligible effects on mood and produced only slightly more side effects than placebo. It is clear from other studies that the subjective effects of cocaine are rarefy detectable in oral doses as low as 10 mg [S]. The systemic bioavailability of oral cocaine is compara~~le to that of intranasal cocaine [15j and in the range of 20-40% of intra~~enous cocaine [5]. On the other hand, cocaine, alone, provided postoperative pain patients with minimal, but negative. mood changes and chronic pain patients with minimal, but positive, mood changes, whereas placebo produced opposing effects. While of questionable statistical and clinical significance. these minor and differential effects contributed to significant interaction effects in terms of selected aspects of mood. These interaction effects were positive in postoperative pain (e.g.. ‘cheerful.’ ‘friendly’) and negative in chronic pain (e.g.. ‘sad, ’ ‘blue,’ ‘serious’). These interaction effects are calculated on the widely held. but largely untested. assumption that the placebo effect is a constant and integral part of each study medication administration. Like opioids, sympathomimetics can produce both ‘euphoric’ and/or ‘dysphoric’ effects, and the quality of their subjective effects are highly dependent upon not only the dose. but the subject and the setting in which the drug is administered [S]. The postoperative and chronic pain patients clearly differed with respect to baseline pain severity and mood and probably also in degree of tolerance to narcotics. Pain was more severe in postoperative patients, but chronic pain patients reported lower scores on the 15-item mood questionnaire. These data show that chronics reported themselves to be less optimistic. shakier, less friendly, less confident, not as happy or calm as postoperative patients. While our study was not designed to determine the sources of patient-dependent differential mood effects, it is not unlikely that such differences are related to differences in the circumstances of acute and chronic pain patients as this relates to pretreatment mood. In conclusion, 10 mg p.o, cocaine is not analgesic nor does it alter morphine effect analgesia in cancer patients with pain. In contrast. there is an interaction between cocaine and morphine in terms of positive alterations in selected aspects of mood in postoperative pain patients and negative alterations in patients with chronic malignant pain. Cocaine alone produced several negative mood changes in postoperative patients, but combined with morphine, interactions in terms of positive mood effects were observed. On the other hand, in patients with chronic pain, cocaine alone produced moderate but positive mood effects, while the combination produced less positive mood changes than did morphine alone. These results,
45
together with those of our previous heroin studies, suggest that the successful use of ‘euphoriant’ elixirs in the management of chronic malignant pain occurs more as a result of excellent symptom management skills than any special property of the particular drugs employed.
References 1 Forrest, Jr., W.H., Brown, Jr., B.W., Brown, C.R., Defalque, R., Gold, M., Gordon, H.E., James, K.E., Katz, J., Mahler, D.L., Schroff, P. and Teutsch, G., Dextroamphetamine with morphine for the treatment of postoperative pain, New EngI. J. Med., 296 (1977) 712-715. S.L. and Rogers, A., Clinical pharmacology of analgesics. I. A method of 2 Houde, R.W., Wallenstein, assaying analgesic effect, Clin. Pharmacol. Ther., 1 (1960) 163-174. 3 Inturrisi, C.E., Max, M.B., Foley, K.M., Schultz, M., Shin, S.-U. and Houde, R.W., The pharmacokinetics of heroin in patients with chronic pain, New EngI. J. Med., 310 (1984) 1213-1217. 4 Inturrisi, C.E., Schultz, M., Shin, S.-U., Umans, J.G., Angel, L. and Simon, E.J., Evidence from opiate binding studies that heroin acts through its metabolites, Life Sci., 33, Suppl. II (1983) 773-776. of cocaine, Nat. Inst. Drug Abuse Res. Monogr., 50 (1984) 34-53. 5 Jones, R., The pharmacology 6 Kaiko, R.F., Wallenstein, S.L., Rogers, A.G., Grabinski, P.Y. and Houde, R.W.. Analgesic and mood effects of heroin and morphine in cancer patients with postoperative pain, New En& J. Med., 304 (1981) 1501-1505. I Kaiko, R.F., Wallenstein, S.L., Rogers, A.G., Grabinski, P.Y. and Houde, R.W., Clinical analgesic studies of intramuscular heroin and morphine in postoperative and chronic cancer pain. In: K.M. Foley and C.E. Inturrisi (Eds.), Opioid Analgesics in the Management of Clinical Pain, Advances in Pain Research and Therapy, Vol. 8, Raven Press, New York, 1986, pp. 107-116. 8 Lasagna, L., Von Felsinger, J.M. and Beecher, H.K., Drug-induced mood changes in man. 1. Observations on healthy subjects, chronically ill patients, and ‘postaddicts,’ J. Amer. med. Ass., 157 (1955) 1006-1020. 9 Melzack, R., Mount, B.M. and Gordon, B.A.. The Brompton mixture versus morphine solution given orally: effects on pain, Canad. med. Ass. J., 120 (1979) 435-438. 10 Melzack, R., Ofiesh, J.G. and Mount, B.M., The Brompton mixture: effects on pain in cancer patients, Canad. med. Ass., J., 115 (1976) 125-129. 11 Mount, B.M., Ajemian, I. and Scott, J.F., Use of the Brompton mixture in treating chronic pain of malignant disease, Canad. med. Ass., J., 115 (1976) 122-124. 12 Twycross, R.G., Effect of cocaine in the Brompton cocktail. In: J. Bonica et al. (Eds.), Advances in Pain Research and Therapy, Vol. 3, Raven Press, New York, 1979, pp. 927-932. 13 Wallenstein, S.L. and Houde, R.W., The clinical evaluation of analgesic effectiveness. In: S. Ehrenpreis and A. Neidle (Eds.), Methods in Narcotic Research, Marcel Dekker, New York. 1975, pp. 127-145. 14 Walsh, T.D., Oral morphine in chronic pain, Pain, 18 (1984) l-11. 15 Wilkinson, P., Van Dyke, C., Jatlow, P., Barash, P. and Byck, R., Intranasal and oral cocaine kinetics, Clin. Pharmacol. Ther., 27 (1980) 386-394. 16 Yang, J.C., Clark, C.C., Dooley, J.C. and Mignogna, F.V., Effect of intranasal cocaine on experimental pain in man, Anesth. Analg., 61 (1982) 358-361.
Pain, 31 (1987) 35-45 Elsevier PA1 01113
Cocaine and ~o~hine interaction in acute and chronic cancer pain 1 Robert F. Kaiko ‘, Ronald Kanner b, Kathleen M. Foley ‘vd, Stanley L. Wallenstein ‘, Anne Marie Cane1 ‘, Ada G. Rogers ’ and Raymond W. Houde ’ Frederick Co., Norwalk, CT (U.S.A.), ‘Albert Einstein College of Medicine, Bronx, NY (U.S.A.), ‘Analgesic Studies Section and Pain Service, Memorial Sloan-Kettering Cancer Center, New York, NY (U.S.A.), and d Cornell University Medicul College, New York, NY (U.S.A.)
’ Purdue
(Received 17 December 1986, revised received and accepted 14 April 1987)
An evaluation of the analgesic, mood and side effects of the combination of intramuscular morphine and oral cocaine was conducted in 17 patients with postoperative pain and 19 others with chronic malignant pain for the purpose of assessing the therapeutic merits of so-called ‘euphoriant’ elixirs in the management of pain in cancer patients. The study was designed as a randomized and double-blind single dose but complete cross-over comparison of the combination of 10 mg intramuscular morphine and 10 mg oral cocaine with morphine alone, cocaine alone, and placebo. While patients clearly discriminated between the analgesic effects of morphine and placebo, there were no differences in the analgesic responses to cocaine and placebo, or in responses to morphine and the combination of morphine and cocaine in either patient group. Side effects were predo~n~tly mo~hine-like and occurred in 59% of patients after the combination, 43% after morphine, 34% after cocaine and 25% after placebo. interaction effects between cocaine and morphine were observed in terms of positive changes toward selected aspects of mood (e.g., cheerful, friendly) in postoperative patients but toward negative aspects of mood (e.g., sad, serious) in patients with chronic pain.
S-arY
Key words: Analgesics; Cancer pain; Postoperative pain
i Supported by USPHS Grants DA-01707, CA-32897 and CA-08748. Previously presented, in part, at the Fourth World Congress on Pain of the International Association for the Study of Pain, Seattle, WA, August 31-September 5, 1984, and at the Forty-Seventh Annual Scientific Meeting of The Committee on Problems of Drug Dependence, Inc., Baltimore, MD, June to-12,1985. Correspondence to: Dr. Kathleen M. Foley, Memorial Sloan-Kettering Avenue, New York, NY 10021, U.S.A.
Cancer Center, 1275 York
0304-3959/87/$03.50 0 1987 Elsevier Science Publishers B.V. (Biomedical Division)
Following successful use of the Brompton’s cocktail in the i~lat~agenlent of chronic malignant pain [lO,ll]. we began a series of studies designed to evaluate the components of this oral (p.0.) mixture for their therapeutic merits. The cocktail, as once employed at St. Christopher’s Hospice in London, contained a mixture of heroin, cocaine, ethyl alcohol, and a phenothiazine. Our studies of heroin following single intramuscular (i.m.) administration in cancer patients with postoperative or chronic malignant pain revealed it to have no unique advantages over currently available analgesics [6,7]. Additional pharmac~~ki~~etic f3] and opiate receptor hinding studies [4] indicate that heroin’s actions are mediated primarily by active metabolites, monoacetylmorphine and morphine. Today, the so-called ‘euphoriant’ elixirs usually consist of aqueous solutions of morphine. alone [14]. This is due. in part, to evidence that the presence of cocaine provides no significant therapeutic advantage in the management of chronic malignant pain 19.121. Both these latter studies, however, lacked an internal control. or intrinsic measure of assay sensitivity. a basic requirement of a meaningful and ~eII-c~)ntrolled study [13J. Definitive conclusions cannot he drawn when ‘no differences’ occur in the absence of an internal control. Intranasal cocaine can, in fact, decrease experimentally induced pain [16] and i.m. dextroamphetamine, another sympathomimetic agent, can double the analgesic potency of morphine in postoperative pain [l]. The objective of the present study was to assess the analgesic efficacy of cocaine in the dose most commonly used in Brompton’s cocktail, and to assess its interaction with morphine in terms of analgesia and other effects in cancer patients with p~~st~~perative and chronic malignant pain.
Methods The study was designed as a randomized, double-blind, single dose, complete cross-over, factorial assay incorporating 4 study medications: placebo, 10 mg p.o. cocaine, 10 mg i.m. mo~hine, and cocaine plus morphine. Procedures and assessment instruments have been previously described in detail [2,6,13]. Briefly, study medications were administered for moderate or severe pain at least 3 h after any prior analgesic, and assessments were obtained at baseline and at 30 and 60 min and hourly thereafter until pain returned to baseline but for no longer than 6 h. Pain intensity and relief were assessed using both categorical and visual analog scales (VAS). Global mood was assessed using a VAS and selected aspects of mood were assessed using a questionnaire consisting of 15 contrasting word/phrase pairs. This latter questionnaire was ad~nistered at baseline and 2 h only in order to limit the stress of questioning on weak and debilitated patients. Spontaneously reported and/or observed side effects were recorded. The study protocol was approved by the Memorial Hospital Institutional Review Board, and all patients who participated in the study gave their written, informed consent. Patients’ reports on their pain, mood, and the occurrence of observed or
31
TABLE
I
PATIENT CHARACTERISTICS AND BASELINE ATIVE AND CHRONIC PAIN STUDY PATIENTS
PAIN
CHARACTERISTICS
Postoperative
Chronic
Males (N) Females (N)
16 1
8 11
Mean age (range)
43 (22-65)
53 (34-67)
61 39
45 55
56 20 11
21 22 16 17 23 2
FOR
POSTOPER-
Baseline pain * Intensity (%) Severe Moderate Site (%) Chest Back Pelvis Abdomen Extremities Head and neck
4 9
Character (%a) Sharp Dull Tight Pulling Throbbing Soreness Crampy Radiating Burning * Incidence
of pre-study
57 33 2 4
26 40 12 15 7 7 2 2
2 2 medication
baseline
pain characteristics
reported
as percent.
reported side effects were obtained by trained .registered nurse observers before the patients received the test medications and at the prescribed intervals thereafter. The demographic and baseline pain characteristics of the patients are summarized in Table I. Thirty-six patients entered the study and 20 completed all data for the 4-way cross-over. Nine postoperative and 11 chronic patients provided these complete data. 17 postoperative and 19 chronic pain patients received a total of 54 and 58 study medications, respectively. The following pain and patient characteristics are based on all patients. Postoperative patients averaged 43 years of age (range, 22-65) and chronic patients, 53 years (range, 34-67). There were disproportionately more men among postoperative (16 men and 1 woman) than among chronic (8 men and 11 women) patients. Patients were receiving a routinely ad~nistered analgesic (e.g., hydromo~hone, oxycodone, morphine or meperidine, most commonly in both groups) prior to and between study medications. The majority of postoperative
patients had thoracotomies and incisional pain in the chest (56%). Pain site was more diverse (e.g., chest, back, abdomen, arms) among chronic patients. Postoperative patients described their pain as sharp in most cases, while chronic patients usually most commonly described their pain as dull, aching and diffuse. Concordantly, postoperative patients categorized their pain as ‘severe‘ more frequently (61%) than chronic patients (45%). In contrast. postoperative patients reported more positive scores than chronic patients on several selected aspects of mood (e.g., pessimistic/optimistic, shaky/serene, angry/friendly, apprehensive/confident. sad/happy and nervous/calm ).
Results Fig. 1 shows time-effect curves in terms of VAS scores for pain intensity, and mood for the 9 postoperative and 11 chronic patients completing
Poetopera~ive Pain
pain the
Chronic Pain
30 OTT----i-
6/O
2
4
6
Hours T’ime-course of pain intensity, pain relief and mood foIIo~ng placebo, morphine, cocaine and the combmation in 9 postoperative and 11 chronic cancer patients with pain. Each point represents the mean visual analog scale score on a 100 mm scale. Solid symbols represent study medications containing morphine. and dashed lines represent study medications containing cocaine. A- - - - -A, morphinetplacebo. cocaine: A ----A*, morphine alone; a- - - - - -A, cocaine alone; A ------A,
39 TABLEII ANALGESICAND MOOD VISUALANALOG SCALES(millimeters)FOLLOWINGPLACEBO, MORPHINE,COCAINEANDTHEIR COMBINATIONIN 9 POSTOPERATIVE AND 11CHRONIC PATIENTS TOTPAR,total pain relief as measured by the area under the pain relief time-effect curve; PID, pain intensity difference (change in pain as compared to pre-treatment intensity differences. Placebo
Morphine
pain level); SPID, sum of pain
Cocaine
Combination
Peak pain relief Postop. Chronic
53 34
63 68
44 39
69 58
TOTPAR Postop. Chronic
90 87
135 193
70 76
161 176
Peak PID Postop. Chronic
31 13
51 42
26 25
51 35
SPID Postop. Chronic
58 22
99 109
35 45
10s 90
Peak change mood Postop. Chronic
14 12
33 23
6 24
28 -11
17 8
-6 11
14 4
Mean change Postop. Chronic
mood
-5 3
4-way cross-over and providing complete data. Morphine, alone, provided greater effects than placebo in terms of all 3 effect measures in both patient groups, while cocaine, alone, was not significantly better than placebo in terms of pain intensity and relief. Higher, but not significantly different, mood scores were observed after cocaine than after placebo in the postoperative patients. The combination of morphine and cocaine was comparable to morphine, alone, for both estimates of analgesia in all patients. Again, higher, but not significantly different mood scores followed the cocaine-containing treatment in the postoperative patients. Table II lists the summary VAS data for peak pain relief, total pain relief (TOTPAR), peak and total pain decrease (Peak PID and SPID), and mood change following each study medication. Analgesic and mood effects of these data were analyzed according to the paradigm in Table III, showing the orthogonal comparisons for the factorial assessment of drug and interaction effects in the two-way analysis of variance. The morphine effect was assessed by ~ompa~son of the two mo~~ne-contai~ng treatments to the treatments not containing morphine. The cocaine effect was assessed similarly. The interaction effect was assessed by com-
40 TABLE
III
~RTHO~~AL FACTORIAL CO~PARIS(~NS EFFECTS DERIVED FROM DA-I-A IN TABLE
OF MAIN Ii
TRE,~TM~NT
AND
iN-r~RA~“rlON
TOTPAR, total pain relief as measured by the area under the pam relief time-effect curt’e: PlD, pain intensity difference (change in pain as compared to pretreatment level): SPID. sum of pain intensit) differences.
~__. Treatments
Morphine
Placebo Morphine Cocaine Combination
I. +
Peak pain relief Postop. Chronic TOTPAR Postop. Chronic Peak PID Postop. Chronic
----__ Effects * cocaine
----_ Interaction
-I-
t t .. 3
35 53(P
135 (f < 0.025) 206 (P < 0.05)
39(PiO.O1) 39 (P i 0.005)
SPID Postop. Chronic
+
5
IS
-15
6 _ 28
46 ._6
11 5
11 - 19
‘- 14 4
32 .- 42
3 -46(P
-’
Peak change mood Postop. Chronic
41 ( P c 0.005) -24
- 13 -34
Mean change mood Postop. Chronic
42 (P < 0.005) -2
4 4
7
-12
* Derived factorial effect vaiues are obtained by summing or subtracting the appropriate means in Table II according to the designated signs in the 3 coIumns above. * Probability values of 0.05 or less are shown in parentheses.
treatment
parison of the morphine/cocaine combination plus placebo to morphine, alone, plus, cocaine, alone. Significant effects on al1 analgesic measures were observed for morphine in both postoperative and chronic pain patients. In contrast, the morphine mood effect was significant only in postoperative patients, and a significant negative peak mood interaction effect was observed only in chronic pain patients. Fig. 2 illustrates the word/phrase pair data from each of the study medications. These data represent mean 2 h minus baseline changes in mood score. The pairs are arranged in descending order of the morphine effect. Generally, morphine produced positive changes, with the exception of a significant change toward ‘apathetic’
41
-1
PUCE60 n +I
F.--+-T
Sad I Happy
+I 0
Shaky i Serene
0
Restless I Peaceful Nervous
I Calm
Uneasy I At ease Blue/Cheerful
3
‘I--
I 0
3 o-+--_ --*
Alone I Sociable
*___-
Apprehensive
ea---
Angry f Friendly Pessimistic
I Optimislic
Heavy I Buoyant Lethargic Apathetic
I Peppy / Enthusiastic *_
-1
I
1
I
COCAINE 0 +l ,
,
COMBINATION -1 0 +I r----m
--b * -* ______+*
I Interested +------‘@ /Amused +I Confident
MORPHINE 0 +1
0
-_,
Uninterested Serious
-1
--0 0
~
*
+-
Q-
+-
I
rs__%
Fig. 2. Zero to 2 h change in contrasting mood word phrase pairs following placebo, morphine, cocaine and the combination in cancer patients with postoperative pain and with chronic pain. Solid symbols and lines represent data from patients with postoperative pain and open symbols and dashed lines represent data from patients with chronic malignant pain. Each point represents the mean difference between the 2 and 0 h scores and is plotted toward the right of the vertical ‘baseline’ if the mean score is positive and toward the left if negative. Asterisks indicate statisticatly significant (P c 0.05, paired two-tailed f test) changes.
feelings among chronic pain patients. Cocaine provided generally positive mood changes in chronic pain, with significance achieved in terms of ‘happy’ and ‘buoyant.’ In contrast, cocaine provided generally negative changes in postoperative pain, with significance achieved in terms of ‘alone.’ The combination of morphine and cocaine provided generally positive mood changes, especially in postoperative pain. On the other hand, as with cocaine alone, placebo appears to have differential mood effects in postoperative pain in comparison to chronic pain. Worsening mood in chronic pain following placebo contrasts with the opposite trends following cocaine. Differential mood effects were examined by factorial analyses of variance of the data from the &item mood questionn~re. The analysis is similar to that carried out on the VAS data in Table III. Fig. 3 shows calculated results. The word/phrase pairs are arranged with the negative aspect on the left and in descending order of the morphine effects. As with the VAS mood data, use of the U-item mood questionnaire resulted in generally positive morphine mood effects but achieved statistical significance in postoperative patients only, while there was a trend toward more positive cocaine effects in chronics than in postoperative patients. Most striking differences were apparent in the consistent differential direction of interaction mood effects. Significant positive interaction effects were observed in postoperative patients in terms of being more ‘cheerful’ and ‘friendly.’ Significant negative
1V
(SE) FOLLOWING PAIN PATIENTS
4 16 4 2s 8
13 6 46 27
12 2 17 2
2 1 1
7
8 3 3
6
M C ~-__-_~-.._._~____I-.~_ 13 16 _
pain
(P). MORPHINE
I
1
12 -I
P
Postoperative
Medication
PLACEBO (PTS)
16 5 31 7
2 2 13 I 54 14
3
1 1 2
4 2 2
16 _
13 _
Chronic
pain
13 6 46 9
3 1
1
14 9 64 20
8
8 1
I~-- 14
MC
_-.___._____ .-_
__~
5
15 6 40 22
_.
C 13
-. . ._-. . .
___
IN POSTOPERATIVE
_. ---- ___--
1 2
-
-__-
-_..
(MC)
4 3 2 4 1 8
15 _
M
--~-___
COMBINATION
-.-----..-
THEIR
P
-
(c’) AND
MC
(M). C‘OCAlNE
* Sedative (sleepy. relaxed. groggy, weak). mental clouding (lightheaded. floating feeling. difficulty concentrating. unable to focu\ .tt!ention. space). disoriented, hazy feeling, feeling of unreality), cardiovascuIar/histammic (sweating, warm feeling, tachycardia. hot. itching). emetic (nausea. vomiting). excitatory (nervous, tense. excited. hypertemion). and other (dry mouth, mlection pam. angry, headache. dyspepsia. dizzy. hiccough>. hungry. difficult> speaking, cold) are listed in terms of the number of occurrences and/or observed.
NPTS N PTS with SE % with SE Total N of SE
Sedative Mental clouding Cardiovascular/histaminic Emetic Excitatory Other
N SE *
_
SIDE EFFECTS AND CHRONIC
TABLE
43
-1
i-
Sad f Happy Blue f Cheerful Uneasy I At ease Alone I Sociable
MORPHINE n
COCAINE 41
-1
d c
rl
Cl
-1
INTERACTION 0 +l
/
,
I
0 Q___-_ d
Q Q__-__ +Q-
Nervous/Calm Uninterested I Interested Shaky I Serene
Q-Q___
Apprehensive I Confident
a--
Restless I Peaceful
c--
Apathetic I Enthusiastic Angry / ~riendiy Lethargic / Peppy Serious / Amused Heavy I Buoyant Pessimistic I Optimistic
---0 4--
c
QCQ______ 0
i+
Fig. 3. Factorial morphine, cocaine and interaction effects in terms of contrasting mood word phrase pair O-2 h changes in cancer patients with postoperative pain and with chronic pain. Solid symbols and lines represent data from patients with postoperative pain and open symbols and dashed lines represent data from patients with chronic malignant pain. Each point represents the mean effect and is plotted toward the right of the vertical line if the mean effect is positive and toward the left if negative. Superscript letters indicate level of statistical significance (P < 0.05 for a, 0.025 for b, 0.01 for c, 0.005 for d, 0.001 for e) from two-way analyses of variance for factorial design with 1 and 35 degrees of freedom. See Table III for procedure for calculating the orthogonal comparisons for morphine, cocaine and interaction effects.
interaction
effects were observed in chronics in terms of being more ‘sad,’ ‘blue’ and “serious.’ Taken together, these two series of analyses demonstrate that the differential interaction effects are related, in part, to differential effects of placebo and cocaine in postoperative and chronic pain, as is graphically indicated by the directions of the arrows for the various mood items in Fig. 2. Table IV shows side effect data for both postoperative and chronic pain patients. The effects were typically morphine-like in most cases. The combination of drugs produced the highest occurrences (percentage of patients with side effects) and both morphine and cocaine, alone, produced higher occurrences than placebo in both patient groups. While the addition of cocaine to morphine was associated with a decrease in the total number of side effects in postoperative patients, the percentage of postoperative patients with side effects was actually higher following the combination. This was related to one patient who reported a large number of ‘mental clouding’ effects following morphine, alone.
Discussion
The dose of cocaine most commonly used in the Brompton’s cocktail had no analgesic effect of its own, nor did it alter the morphine analgesia. These results are
44
consistent with those of other investigators who found no differences tn analgesi:l with the addition of 10 mg p.o. cocaine to morphine or heroin in the m;magetnent or chronic malignant pain [9,12]. Omission of an internal measure of assay sensitivit> from these latter studies, however, made us question whether or not those studies were sufficiently sensitive to detect clinicall> significant differencex. The ;Ibility (if patients to discriminate clearly between the analgesic effects of tnt~rphit~e ‘and placebo provided a measure of sensitivity in the current study. It is not unfikel! that. at higher doses. cocaine could increabe the effectiveness of morphine in 3 similar manner as dextroamphetamine [ 1J. Cocaine, alone, had negligible effects on mood and produced only slightly more side effects than placebo. It is clear from other studies that the subjective effects of cocaine are rarefy detectable in oral doses as low as 10 mg [S]. The systemic bioavailability of oral cocaine is compara~~le to that of intranasal cocaine [15j and in the range of 20-40% of intra~~enous cocaine [5]. On the other hand, cocaine, alone, provided postoperative pain patients with minimal, but negative. mood changes and chronic pain patients with minimal, but positive, mood changes, whereas placebo produced opposing effects. While of questionable statistical and clinical significance. these minor and differential effects contributed to significant interaction effects in terms of selected aspects of mood. These interaction effects were positive in postoperative pain (e.g.. ‘cheerful.’ ‘friendly’) and negative in chronic pain (e.g.. ‘sad, ’ ‘blue,’ ‘serious’). These interaction effects are calculated on the widely held. but largely untested. assumption that the placebo effect is a constant and integral part of each study medication administration. Like opioids, sympathomimetics can produce both ‘euphoric’ and/or ‘dysphoric’ effects, and the quality of their subjective effects are highly dependent upon not only the dose. but the subject and the setting in which the drug is administered [S]. The postoperative and chronic pain patients clearly differed with respect to baseline pain severity and mood and probably also in degree of tolerance to narcotics. Pain was more severe in postoperative patients, but chronic pain patients reported lower scores on the 15-item mood questionnaire. These data show that chronics reported themselves to be less optimistic. shakier, less friendly, less confident, not as happy or calm as postoperative patients. While our study was not designed to determine the sources of patient-dependent differential mood effects, it is not unlikely that such differences are related to differences in the circumstances of acute and chronic pain patients as this relates to pretreatment mood. In conclusion, 10 mg p.o, cocaine is not analgesic nor does it alter morphine effect analgesia in cancer patients with pain. In contrast. there is an interaction between cocaine and morphine in terms of positive alterations in selected aspects of mood in postoperative pain patients and negative alterations in patients with chronic malignant pain. Cocaine alone produced several negative mood changes in postoperative patients, but combined with morphine, interactions in terms of positive mood effects were observed. On the other hand, in patients with chronic pain, cocaine alone produced moderate but positive mood effects, while the combination produced less positive mood changes than did morphine alone. These results,
45
together with those of our previous heroin studies, suggest that the successful use of ‘euphoriant’ elixirs in the management of chronic malignant pain occurs more as a result of excellent symptom management skills than any special property of the particular drugs employed.
References 1 Forrest, Jr., W.H., Brown, Jr., B.W., Brown, C.R., Defalque, R., Gold, M., Gordon, H.E., James, K.E., Katz, J., Mahler, D.L., Schroff, P. and Teutsch, G., Dextroamphetamine with morphine for the treatment of postoperative pain, New EngI. J. Med., 296 (1977) 712-715. S.L. and Rogers, A., Clinical pharmacology of analgesics. I. A method of 2 Houde, R.W., Wallenstein, assaying analgesic effect, Clin. Pharmacol. Ther., 1 (1960) 163-174. 3 Inturrisi, C.E., Max, M.B., Foley, K.M., Schultz, M., Shin, S.-U. and Houde, R.W., The pharmacokinetics of heroin in patients with chronic pain, New EngI. J. Med., 310 (1984) 1213-1217. 4 Inturrisi, C.E., Schultz, M., Shin, S.-U., Umans, J.G., Angel, L. and Simon, E.J., Evidence from opiate binding studies that heroin acts through its metabolites, Life Sci., 33, Suppl. II (1983) 773-776. of cocaine, Nat. Inst. Drug Abuse Res. Monogr., 50 (1984) 34-53. 5 Jones, R., The pharmacology 6 Kaiko, R.F., Wallenstein, S.L., Rogers, A.G., Grabinski, P.Y. and Houde, R.W.. Analgesic and mood effects of heroin and morphine in cancer patients with postoperative pain, New En& J. Med., 304 (1981) 1501-1505. I Kaiko, R.F., Wallenstein, S.L., Rogers, A.G., Grabinski, P.Y. and Houde, R.W., Clinical analgesic studies of intramuscular heroin and morphine in postoperative and chronic cancer pain. In: K.M. Foley and C.E. Inturrisi (Eds.), Opioid Analgesics in the Management of Clinical Pain, Advances in Pain Research and Therapy, Vol. 8, Raven Press, New York, 1986, pp. 107-116. 8 Lasagna, L., Von Felsinger, J.M. and Beecher, H.K., Drug-induced mood changes in man. 1. Observations on healthy subjects, chronically ill patients, and ‘postaddicts,’ J. Amer. med. Ass., 157 (1955) 1006-1020. 9 Melzack, R., Mount, B.M. and Gordon, B.A.. The Brompton mixture versus morphine solution given orally: effects on pain, Canad. med. Ass. J., 120 (1979) 435-438. 10 Melzack, R., Ofiesh, J.G. and Mount, B.M., The Brompton mixture: effects on pain in cancer patients, Canad. med. Ass., J., 115 (1976) 125-129. 11 Mount, B.M., Ajemian, I. and Scott, J.F., Use of the Brompton mixture in treating chronic pain of malignant disease, Canad. med. Ass., J., 115 (1976) 122-124. 12 Twycross, R.G., Effect of cocaine in the Brompton cocktail. In: J. Bonica et al. (Eds.), Advances in Pain Research and Therapy, Vol. 3, Raven Press, New York, 1979, pp. 927-932. 13 Wallenstein, S.L. and Houde, R.W., The clinical evaluation of analgesic effectiveness. In: S. Ehrenpreis and A. Neidle (Eds.), Methods in Narcotic Research, Marcel Dekker, New York. 1975, pp. 127-145. 14 Walsh, T.D., Oral morphine in chronic pain, Pain, 18 (1984) l-11. 15 Wilkinson, P., Van Dyke, C., Jatlow, P., Barash, P. and Byck, R., Intranasal and oral cocaine kinetics, Clin. Pharmacol. Ther., 27 (1980) 386-394. 16 Yang, J.C., Clark, C.C., Dooley, J.C. and Mignogna, F.V., Effect of intranasal cocaine on experimental pain in man, Anesth. Analg., 61 (1982) 358-361.