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NSAID: Clinical aspects
Vol. 3 No. j Summer 1988
Journal of Pain and SymptomManagenaent
33
34
CD Harming, G Smith, Department of Leicester, UK and N Graham, Applied Chemistry, University Scotland.
of Anaesthesia, University M McNeill, Department of of Strathclyde, Glasgow,
The morphine hydrogel suppository (MHS) is a new sustained release formulation. Morphine is held within a biologically inert hydrophilic polymer matrix and released on hydration within the rectum at a controlled and predictable rate. Preliminary studies' with several prototy,oes resulted in a formulation which has an initial bolus release followed by a constant release for a 12h period (MHS(B)). The formulation was able to attain and maintain plasma morphine concentrations close to those normally associated with adequate postoperative analgesia. A sustained release only preparation (MHS(S)) was able to maintain that concentration for a further 12h. Clinical observation suggested improved pain control with a reduction in nausea and vomiting. Further evaluation has awaited the availability of a consistent product in sufficient quantities to permit large scale studies. A double blind, placebo controlled trial is planned in women undergoing abdominal hysterectomy to evaluate the utility of MHS as a premedicant and as the postoperative analgesic. MHS has clear applications to the management of chronic pain and two studies are proposed to investigate its clinical utility and pharmacokinetics. The simplicity of administration, reduced liability for diversion to illegal use and the independence from upper GI tnotibility are all possible benefits. 1.
Hanning
et
al.,
Br
J Anaesth.
'988:
60;
in press.
36
35 NSAID:
BIOAVAILABILITY OF HEROIN IN CANCER PATIENTS AFTER REPEATED ORAL DOSING. 0. Saltsburg, C.E. Inturrisi, R. Greenslade, J. Lapin, T. Nip and K.M. Foley, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 USA. In humans, heroin (HI is rapidly biotransformed to the active metabolites 6-acetylmorphine (6-A&l) and morphine IM). We have previously reported (NEJM 310:1213,1984) that after a single oral dose of H, N but not H or 6-A& is measurable in patient (pt) blood samples. Furthermore, crossover single dose studies have revealed that oral H provides slightly less systemic morphine than does an equimolar oral dose of M. In the present study, we administered oral H to 17 cancer pain pts to determine if H and its metabolites are present in blood after repeated oral dosing. H dose was titrated to provide adequate analgesia lasting a minimum of 3-4 hrs. On approaching steady state conditions, the study phase was begun by obtaining blood samples just prior to the next administered dose of H (trough level) and at selected times thereafter (15, 30, 60, 180 and 240 mins). 15 pts completed the study. Ln 6 pts. medication with Ii was continued after the test dose and the study was repeated after a second test dose administered a minimum of 24 hrs from the first. Male to female ratio was 2:1, with an average age of 54213 yrs (SD). Mean pt weight was 71+18kg (SD). In the 24 hrs prior to the collection of the first set of blood levels (trough level), mean H usage was 203+168mg (SD) of H, with a range from 80 to 690 mg. Only 1 of 15 pts had measurable blood levels of fi (31 rig/ml at peak). 14 of 15 patients had measurable blood levels of M (12 to 62 rig/ml at peak) and 4 of 15 pts had measurable blood levels of 6-AN (12 to 71 "g/ml at peak). These results indicate that repetitive oral dosing with H does not result in measurable blood levels of H or 6-AN in most cancer pain pts. In accord with our previous data, these data suggest that H acts as a prodrug, with rapid presystemic biotransformation to 6-AM and M.
CLINICAL
F DE CONNO Division of Cancer Institute,
ASPECTS Pain
Therapy and Milan, Italy.
Palliative
Care,
Nationai
The author presents a clinical experience carried out in a palliative care unit on the treatment of cancer pain by means of NSAID drugs, which have been administered alone or in association with narcotics following WHO guidelines. On the basis of previous studies an analysis is carried out on how NSAID can control serious pain for periods over 3 weeks, even when given alone. An original comparative study is also preserted on 3 NSAID: Suprofen, Diclofenac, Indomethacin, Paracetamol, Pirprofen, ASA, Naproxen, Ibuprofen, Sulindac. in Drugs have been administered in double blind and following a precross over to 72 patients for 2 weeks, fixed protocol of randomization. Analgesic results have been compared and tolerability of all drugs has been evaluated. The degree of satisfaction expressed subjectively by the patient is also examined. The authors conclude by stressing the importance of NSAID administered alone or in association for the controi of pain due to the invasion of serosas, periostium, derma, muscle fasciae, and articulsr gland by the tumoral mass.
REMATOLGGICSAFETYASSOCIATEDWITH TRE ADMINISTRATION OF CHOLINE MAGNESIUM TRISALICYLATE. C. Cronin, R. Kaiko, R. Grandy, G. Thomas, P. Goldenheim, The Purdue Frederick Company, Norwalk CT 06856, USA. Since many salicylates and non-steroidal antiinflammatory drugs (NSAIDs) cause hematologic side effects, their use may be precluded in many patients requiring analgesic therapy. One NSAID, choline magnesium trisalicylate (CMT), a non-acetylated salicylate, has previously been reported not to interfere with platelet aggregation. To confirm these findings as well as to evaluate the effect of CMT on other hematologic indices, we conducted an evaluation of CMT and aspirin (ASA) on bleeding time, prothrombin time, platelet count and platelet aggregation in 30 healthy subjects. CWT (1500 mg q12h) and ASA (650 mg q4h) were administered Over 5 days after a 3 day baseline evaluation. Results demonstrated that neither drug produced changes in prothrombin time or platelet count. ASA caused an increase (~~0.05) in bleeding time (from baseline of 2.7 mins to Wean bleeding time active mean of 3.5 mins). remained the same after CMT adminstration as Changes in nine seen at baseline (2.6 mins). subjects from normal to abnormal with drug were seen in the platelet aggregation studies; 8 with ASA and 1 with CWT. We concluded that CWTdoes not adversely affect hematologic parameters and should be considered first line therapy in patients with concomitant hematologio abnormalities who require NSAID therapy.
Journal of Pain and SymptomManagenaent
33
34
CD Harming, G Smith, Department of Leicester, UK and N Graham, Applied Chemistry, University Scotland.
of Anaesthesia, University M McNeill, Department of of Strathclyde, Glasgow,
The morphine hydrogel suppository (MHS) is a new sustained release formulation. Morphine is held within a biologically inert hydrophilic polymer matrix and released on hydration within the rectum at a controlled and predictable rate. Preliminary studies' with several prototy,oes resulted in a formulation which has an initial bolus release followed by a constant release for a 12h period (MHS(B)). The formulation was able to attain and maintain plasma morphine concentrations close to those normally associated with adequate postoperative analgesia. A sustained release only preparation (MHS(S)) was able to maintain that concentration for a further 12h. Clinical observation suggested improved pain control with a reduction in nausea and vomiting. Further evaluation has awaited the availability of a consistent product in sufficient quantities to permit large scale studies. A double blind, placebo controlled trial is planned in women undergoing abdominal hysterectomy to evaluate the utility of MHS as a premedicant and as the postoperative analgesic. MHS has clear applications to the management of chronic pain and two studies are proposed to investigate its clinical utility and pharmacokinetics. The simplicity of administration, reduced liability for diversion to illegal use and the independence from upper GI tnotibility are all possible benefits. 1.
Hanning
et
al.,
Br
J Anaesth.
'988:
60;
in press.
36
35 NSAID:
BIOAVAILABILITY OF HEROIN IN CANCER PATIENTS AFTER REPEATED ORAL DOSING. 0. Saltsburg, C.E. Inturrisi, R. Greenslade, J. Lapin, T. Nip and K.M. Foley, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 USA. In humans, heroin (HI is rapidly biotransformed to the active metabolites 6-acetylmorphine (6-A&l) and morphine IM). We have previously reported (NEJM 310:1213,1984) that after a single oral dose of H, N but not H or 6-A& is measurable in patient (pt) blood samples. Furthermore, crossover single dose studies have revealed that oral H provides slightly less systemic morphine than does an equimolar oral dose of M. In the present study, we administered oral H to 17 cancer pain pts to determine if H and its metabolites are present in blood after repeated oral dosing. H dose was titrated to provide adequate analgesia lasting a minimum of 3-4 hrs. On approaching steady state conditions, the study phase was begun by obtaining blood samples just prior to the next administered dose of H (trough level) and at selected times thereafter (15, 30, 60, 180 and 240 mins). 15 pts completed the study. Ln 6 pts. medication with Ii was continued after the test dose and the study was repeated after a second test dose administered a minimum of 24 hrs from the first. Male to female ratio was 2:1, with an average age of 54213 yrs (SD). Mean pt weight was 71+18kg (SD). In the 24 hrs prior to the collection of the first set of blood levels (trough level), mean H usage was 203+168mg (SD) of H, with a range from 80 to 690 mg. Only 1 of 15 pts had measurable blood levels of fi (31 rig/ml at peak). 14 of 15 patients had measurable blood levels of M (12 to 62 rig/ml at peak) and 4 of 15 pts had measurable blood levels of 6-AN (12 to 71 "g/ml at peak). These results indicate that repetitive oral dosing with H does not result in measurable blood levels of H or 6-AN in most cancer pain pts. In accord with our previous data, these data suggest that H acts as a prodrug, with rapid presystemic biotransformation to 6-AM and M.
CLINICAL
F DE CONNO Division of Cancer Institute,
ASPECTS Pain
Therapy and Milan, Italy.
Palliative
Care,
Nationai
The author presents a clinical experience carried out in a palliative care unit on the treatment of cancer pain by means of NSAID drugs, which have been administered alone or in association with narcotics following WHO guidelines. On the basis of previous studies an analysis is carried out on how NSAID can control serious pain for periods over 3 weeks, even when given alone. An original comparative study is also preserted on 3 NSAID: Suprofen, Diclofenac, Indomethacin, Paracetamol, Pirprofen, ASA, Naproxen, Ibuprofen, Sulindac. in Drugs have been administered in double blind and following a precross over to 72 patients for 2 weeks, fixed protocol of randomization. Analgesic results have been compared and tolerability of all drugs has been evaluated. The degree of satisfaction expressed subjectively by the patient is also examined. The authors conclude by stressing the importance of NSAID administered alone or in association for the controi of pain due to the invasion of serosas, periostium, derma, muscle fasciae, and articulsr gland by the tumoral mass.
REMATOLGGICSAFETYASSOCIATEDWITH TRE ADMINISTRATION OF CHOLINE MAGNESIUM TRISALICYLATE. C. Cronin, R. Kaiko, R. Grandy, G. Thomas, P. Goldenheim, The Purdue Frederick Company, Norwalk CT 06856, USA. Since many salicylates and non-steroidal antiinflammatory drugs (NSAIDs) cause hematologic side effects, their use may be precluded in many patients requiring analgesic therapy. One NSAID, choline magnesium trisalicylate (CMT), a non-acetylated salicylate, has previously been reported not to interfere with platelet aggregation. To confirm these findings as well as to evaluate the effect of CMT on other hematologic indices, we conducted an evaluation of CMT and aspirin (ASA) on bleeding time, prothrombin time, platelet count and platelet aggregation in 30 healthy subjects. CWT (1500 mg q12h) and ASA (650 mg q4h) were administered Over 5 days after a 3 day baseline evaluation. Results demonstrated that neither drug produced changes in prothrombin time or platelet count. ASA caused an increase (~~0.05) in bleeding time (from baseline of 2.7 mins to Wean bleeding time active mean of 3.5 mins). remained the same after CMT adminstration as Changes in nine seen at baseline (2.6 mins). subjects from normal to abnormal with drug were seen in the platelet aggregation studies; 8 with ASA and 1 with CWT. We concluded that CWTdoes not adversely affect hematologic parameters and should be considered first line therapy in patients with concomitant hematologio abnormalities who require NSAID therapy.