DOSE-RESPONSE PHARMACOLOGY OF INTRATHECAL MORPHINE IN HUMAN VOLUNTEERS

Background: Intrathecal morphine sulfate (ITMS) administration was int roduced into clinical practice in 1979. Inadequate information exists delineating ITMS respiratory effects in the dosage range most frequent ly employed today. This study evaluated 0.2, 0.4, and 0.6 mg ITMS in m ale volunteers. Methods: Twenty healthy, young, adult male volunteers received 0.0, 0.2, 0.4, or 0.6 mg preservative-free ITMS in an isobari c solution administered at the L3-L4 interspace in a double-blind rand omized fashion. Respiratory function was assessed by finger pulse oxim etry (Sp(O2)), respiratory rate, and arterial blood gas analysis via a n indwelling arterial catheter and the slope of the ventilatory respon se to carbon dioxide (V(E)/CO2). Analgesia was assessed by the effect of ITMS on moderate pain produced by pressure algometry at the tibia. The need for supplemental oxygen, 2 L/min via nasal cannulae, was dete rmined by the failure of verbal and tactile prompts to maintain subjec ts' Sp(O2) greater-than-or-equal-to 85% on more than two occasions. He art rate, arterial blood pressure, sedation level, pupil size, and the incidence of adverse effects also were documented. All the above meas urements were made before and 30 min after ITMS, hourly for 11 h, and then every 2 h for 12 more h. Results: ITMS produced significant dose- related decreases in Sp(O2). Mild desaturations (Sp(O2) greater-than-o r-equal-to 85 and < 90%) occurred in 2 of 5, 3 of 5, and 4 of 5 subjec ts receiving 0.2, 0.4, and 0.6 mg ITMS, respectively. Moderate to seve re desaturations (Sp(O2) < 85%) occurred in 0 of 5, 2 of 5, and 4 of 5 subjects receiving 0.2, 0.4, and 0.6 mg ITMS, respectively. The need for supplemental oxygen also was significantly related to ITMS dose, w ith 0 of 5, 1 of 5, and 4 of 5 subjects requiring oxygen after 0.2, 0. 4, and 0.6 mg ITMS, respectively. Nasal oxygen administration consiste ntly alleviated hypoxemia. Increases in arterial carbon dioxide tensio n (Pa(CO2)) and decreases in pH were significantly related to ITMS dos e. Peak mean Pa(CO2)s were 42.4, 44.9, and 50.7 mmHg in the 0.2-, 0.4- , and 0.6-mg groups, respectively. These peaks occurred 6.5-7.5 h afte r ITMS injection. ITMS produced significant dose-related depression of V(E)/CO2. Maximum mean depressions of V(E)/CO2 were to 61%, 63%, and 32% of baseline in the 0.2-, 0.4-, and 0.6-mg groups, respectively. Th ese nadirs occurred 3.5-7.5 h after ITMS injection. Some subjects rece iving 0.6 mg ITMS experienced profound (<20% of baseline) and prolonge d (<50% of baseline for up to 20 h) V(E)/CO2 depression. Magnitude and duration of analgesia after ITMS were dose-related. Changes in heart rate, systolic blood pressure, and respiratory rate were not significa ntly related to ITMS dose. Hypoxemia was not related to respiratory ra te. Although ITMS produced statistically significant dose-related incr eases in sedation and decreases in pupil size, these changes were smal l and did not coincide with hypoxemia. ITMS caused dose-related increa ses in emesis, but the severity of pruritus and urinary retention was unrelated to dose. Conclusion: ITMS produced dose-related analgesia an d respiratory depression in nonsurgical healthy, young, adult male vol unteers. Respiratory depression was significant after 0.2 or 0.4 mg an d profound and prolonged after 0.6 mg. No clinical signs or symptoms, including respiratory rate, reliably indicated hypoxemia. Pulse oximet ry reliably detected hypoxemia after ITMS, and supplemental nasal oxyg en (2 L/min) effectively corrected this hypoxemia.