The neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) and morphine act independently on the control of breathing

Inhibitors of nitric oxide synthase (NOS) have analgesic properties and reduce opioid tolerance and dependency. To investigate a possible interaction of NOS inhibitors with the respiratory depressant action of morphine, we determined the effects of the neuronal NOS inhibitor 7- nitroindazole (7-NI) on the ventilatory carbon dioxide response curve; subsequently, we studied the effects of additional morphine application. Finally, using naloxone, we investigated a possible interaction (at the opioid receptor) between the effects of 7-NI and morphine. The effects of 7-NI 50 mg kg-1 i.p., morphine 0.1 mg kg-1 i.v. and naloxone 0.1 mg kg-1 i.v. were studied using dynamic end-tidal carbon dioxide forcing in eight cats under alpha-choralose-urethane anaesthesia. Data analysis was performed using a two-compartment model comprising a fast peripheral and a slow central component characterized by carbon dioxide sensitivities and a single offset B (apnoeic threshold). 7-NI decreased the mean apnoeic threshold from 4.27 (SD 0.87) to 2.59 (1.71) kPa. Peripheral and central carbon dioxide sensitivities were reduced from 0.56 (0.22) to 0.26 (0.09) litre min-1 kPa-1 and from 0.09 (0.05) to 0.04 (0.03) litre min-1 kPa-1, respectively. Morphine increased the apnoeic threshold by 0.5 kPa and reduced carbon dioxide sensitivity by a further 35%. Naloxone reversed the ventilatory effects of morphine but not those induced by 7-NI. We conclude that the respiratory effects of 7-NI and morphine are mediated independently and that the effects of 7-NI do not result from interaction with opioid receptors.      

Simultaneous measurement and integrated analysis of analgesia and respiration after an intravenous morphine infusion

BACKGROUND: To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans. METHODS: Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion. At regular time intervals, respiratory variables (breathing at a fixed end-tidal partial pressure of carbon dioxide of 50 mmHg and the isocapnic acute hypoxic response), pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 24 h. Population pharmacokinetic (sigmoid Emax)-pharmacodynamic models were applied to the respiratory and pain data. The models are characterized by potency parameters, shape parameters (gamma), and blood-effect site equilibration half-lives. All collected data were analyzed simultaneously using the statistical program NONMEM. RESULTS: Placebo had no systematic effect on analgesic or respiratory variables. Morphine potency parameter and blood-effect site equilibration half-life did not differ significantly among the three measured effect parameters (P > 0.01). The integrated NONMEM analysis yielded a potency parameter of 32 +/- 1.4 nm (typical value +/- SE) and a blood-effect site equilibration half-life of 4.4 +/- 0.3 h. Parameter gamma was 1 for hypercapnic and hypoxic breathing but 2.4 +/- 0.7 for analgesia (P < 0.01). CONCLUSIONS: Our data indicate that systems involved in morphine-induced analgesia and respiratory depression share important pharmacodynamic characteristics. This suggests similarities in central mu-opioid analgesic and respiratory pathways (e.g., similarities in mu-opioid receptors and G proteins). The clinical implication of this study is that after morphine administration, despite lack of good pain relief, moderate to severe respiratory depression remains possible.     

Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and mu-opioid receptor deficient mice

Background. Morphine-6-glucuronide (M6G) is a metabolite ofmorphine with potent analgesic properties. The influence ofM6G on respiratory and antinociceptive responses was investigatedin mice lacking the µ-opioid receptor (MOR) and comparedwith morphine. Methods. Experiments were performed in mice lacking exon 2 ofthe MOR (n=18) and their wild type (WT) littermates (n=20).The influence of M6G and morphine on respiration was measuredusing whole body plethysmography during three elevations ofinspired carbon dioxide. Antinociception was assessed usingtail flick and hotplate tests. Results. In WT but not null mutant mice, a dose-dependent depressionof the slope of the ventilatory carbon dioxide response wasobserved after M6G and morphine. Similarly, both opioids weredevoid of antinociceptive effects in null mutant mice, but showedpotent dose-dependent analgesia in WT animals. Potency differencesbetween M6G and morphine in WT mice were of the same order ofmagnitude for analgesia and respiration. Conclusions. The data indicate that the desired (antinociceptive)and undesired (respiratory depression) effects of M6G and morphineare linked to the same gene product; that is the MOR. Otheropioid- and non-opioid-receptor systems may play a minor rolein the actions of M6Gs and morphine. The clinical implicationsof our findings are that any agent acting at the MOR will invariablycause (potent) analgesia in combination with (variable) respiratorydepression. Br J Anaesth 2003; 91: 862–70     

Influence of Acute Pain Induced by Activation of Cutaneous Nociceptors on Ventilatory Control

Background: Although many studies show that pain increases breathing, they give little information on the mechanism by which pain interacts with ventilatory control. The authors quantified the effect of experimentally induced acute pain from activation of cutaneous nociceptors on the ventilatory control system.

Methods: In eight volunteers, the influence of pain on various stimuli was assessed: room air breathing, normoxia (end-tidal pressure of carbon dioxide (PETCO2) clamped, normoxic and hyperoxic hypercapnia, acute hypoxia, and sustained hypoxia (duration, 15-18 min; end-tidal pressure of oxygen, approximately 53 mmHg). Noxious stimulation was administered in the form of a 1-Hz electric current applied to the skin over the tibial bone.

Results: While volunteers breathed room air, pain increased ventilation (V with dotI) from 10.9 +/- 1.7 to 12.9 +/- 2.5 l/min sup -1 (P < 0.05) and reduced PETCO2 from 38.3 +/- 2.3 to 36.0 +/- 2.3 mmHg (P < 0.05). The increase in V with dotI due to pain did not differ among the different stimuli. This resulted in a parallel leftward-shift of the V with dotI -carbon dioxide response curve in normoxia and hyperoxia, and in a parallel shift to higher V with dotI levels in acute and sustained hypoxia.     

Severe personality disorders associated with addictive behavior]

After demonstrating the failure of a one dimensional approach to treating addictive behavior coupled with severe personality disorders, the authors suggest an organization of services based on the systemic approach. They recommend a personalized program with both external and internal services. With this in mind, the authors present a program developed by professionals involved in the fields of mental health and addictive behavior. Co-ordinated by a multidisciplinary team, it requires a specific contribution from all members of the team who are involved in different aspects of the person's life. To locate potential users of the program, brochures are sent to CLSCs (community health centres), hospitals, public and private resources, AIDS programs, social workers, and community health workers. Once in treatment, the patient goes through various treatment zones. The first, labelled the reception zone is designated with the initial contact between client and the program. In many instances, a significant other who is close to the client is contacted to take part in the program and help. In the zone of clarification, the client must come to terms with the program and indicate a serious determination to see the program through. The development zone centers on an active reflection of self and the development of new abilities for interpersonal relations, assisting the individual to function autonomously. The goal is for clients to attain a level of self-criticism of their own addiction. The zone of consolidation is optimally reached after about one year in the program. Clients are able to integrate everything learned in the development zone and apply it to their daily life. Community organizations are involved at this stage. The authors conclude that a multidimensional approach, a concerted commitment and a recognition of the contribution of all team members involved in the treatment, are essential elements for tangible results.     

Sex Differences in Morphine-induced Ventilatory Depression Reside within the Peripheral Chemoreflex Loop

Background: This study gathers information in humans on the sites of sex-related differences in ventilatory depression caused by the [micro sign]-opioid receptor agonist morphine.

Methods: Experiments were performed in healthy young men (n = 9) and women (n = 7). Dynamic ventilatory responses to square-wave changes in end-tidal carbon dioxide tension (7.5-15 mmHg) and step decreases in end-tidal oxygen tension (step from 110 to 50 mmHg, duration of hypoxia 15 min) were obtained before and during morphine infusion (intravenous bolus dose 100 [micro sign]g/kg, followed by 30 [micro sign]g [middle dot] kg-1 [middle dot] h-1). Each hypercapnic response was separated into a fast peripheral and slow central component, which yield central (Gc) and peripheral (Gp) carbon dioxide sensitivities. Values are mean +/- SD.

Results: In carbon dioxide studies in men, morphine reduced Gc from 1.61 +/- 0.33 to 1.23 +/- 0.12 l [middle dot] mmHg-1 (P < 0.05) without affecting Gp (control, 0.41 +/- 0.16 and morphine, 0.49 +/- 0.12 l [middle dot] [middle dot] min-1 [middle dot] mmHg-1, not significant). In carbon dioxide studies in women, morphine reduced Gc, from 1.51 +/- 0.74 to 1.17 +/- 0.52 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05), and Gp, from 0.54 +/- 0.19 to 0.39 +/- 0.22 l [middle dot] min-1 [middle dot] mmHg-1 (P < 0.05). Morphine-induced changes in Gc were equal in men and women; changes in Gp were greater in women. In hypoxic studies, morphine depressed the hyperventilatory response at the initiation of hypoxia more in women than in men (0.54 +/- 0.23 vs. 0.26 +/- 0.34 l [middle dot] min-1 [middle dot] %-1, respectively; P < 0.05). The ventilatory response to sustained hypoxia (i.e., 15 min) did not differ between men and women.     

Simultaneous Measurement and Integrated Analysis of Analgesia and Respiration after an Intravenous Morphine Infusion

Background: To study the influence of morphine on chemical control of breathing relative to the analgesic properties of morphine, the authors quantified morphine-induced analgesia and respiratory depression in a single group of healthy volunteers. Both respiratory and pain measurements were performed over single 24-h time spans.

Methods: Eight subjects (four men, four women) received a 90-s intravenous morphine infusion; eight others (four men, four women) received a 90-s placebo infusion. At regular time intervals, respiratory variables (breathing at a fixed end-tidal partial pressure of carbon dioxide of 50 mmHg and the isocapnic acute hypoxic response), pain tolerance (derived from a transcutaneous electrical acute pain model), and arterial blood samples were obtained. Data acquisition continued for 24 h. Population pharmacokinetic (sigmoid Emax)-pharmacodynamic models were applied to the respiratory and pain data. The models are characterized by potency parameters, shape parameters ([gamma]), and blood-effect site equilibration half-lives. All collected data were analyzed simultaneously using the statistical program NONMEM.

Results: Placebo had no systematic effect on analgesic or respiratory variables. Morphine potency parameter and blood-effect site equilibration half-life did not differ significantly among the three measured effect parameters (P > 0.01). The integrated NONMEM analysis yielded a potency parameter of 32 +/- 1.4 nm (typical value +/- SE) and a blood-effect site equilibration half-life of 4.4 +/- 0.3 h. Parameter [gamma] was 1 for hypercapnic and hypoxic breathing but 2.4 +/- 0.7 for analgesia (P < 0.01).