Analgesic and Nonanalgesic Effects of Intravenous Hydromorphone ‐ Relation to Plasma Concentrations in Healthy Volunteers

Abstract

Analgesic and nonanalgesic effects ofintravenous hydromorphone -Relation to plasma concentrations in healthy volunteers. Pain Res Manage 1996;1(2):86-92.OBJECTIVE: To investigate the analgesic and nonanalgesic effects and the pharmacokinetics of an intravenous infusion of 2 mg hydromorphone over 20 mins. DESIGN: Open study. SUBJECTS: Twelve healthy volunteers. MEASUREMENTS: The analgesic effect of hydromorphone was evaluated serially using pressure pain thresholds (PPTs) measured on the third fingers and toes. The nonanalgesic effects of hydromorphone were measured as miosis, decrease of saliva production and central nervous effects such as euphoria/dysphoria, nausea, headache, fatigue and feeling of heaviness. Plasma concentration of hydromorphone was measured using high performance liquid chromatography. RES UL TS: PPTs were significantly increased compared with baseline levels for up to 2 h after the infusion of hydromorphone. Significant miosis and reduction of saliva production were registered up to 6 h after drug administration. Fatigue and heaviness were reported by all subjects. In the studied opioid-naive subjects, the hydromorphone-induced analgesic effect was of shorter duration than the studied nonanalgesic effects. The terminal elimination half-life of hydromorphone was 1.87±0.4 h (± SD) (95% CI 1.61 to 2.13), systemic clearance was 1.81±0.25 L/min (95% CI 1.65 to 1.97) and volume of distribution was 4.15±0.86 L/kg (95% CI 3.6 to 4.71). CONCLUSION: Analgesia and nonanalgesic effects appear to be well correlated with the plasma concentrations of the hydromorphone. MESURES : L' effet analgesique de l 'hydromorphone a ete evalue en series en utilisant les seuils de la douleur a la pression mesures sur le majeur et le gros orteil. Les effets non analgesiques de l 'hydromorphone ont ete mesures en tant que myosis, diminution de la production de salive et effets du systeme nerveux central tels I' euphorie ou la dysphorie, la nausee, les cephalees, la fatigue et la sensation de lourdeur. La concentration plasmatique d'hydromorphone a ete mesuree par chromatographie haute performance. RESULT A TS : Les seuils de la douleur a la pression augmentaient considerablement comparativement aux valeurs de base jusqu'a deux heures apres la perfusion d 'hydromorphone. Un myosis important ainsi qu'une diminution de la production de salive ont ete enregistres jusqu'a 6 h apres !'administration du medicament. La fatigue et la sensation de lourdeur ont ete rapportees par tous les sujets. Dans le groupe etudie de sujets naifs a l'opio"ide, l'effet analgesique induit par l'hydromorphone persistait moins longtemps que les effets non analgesiques etudies. La demi-vie d'elimination finale de l'hydromorphone etait de 1,87±0,4 h (±ecart-type) (IC 95 % 1,61-2,13), la clairance systemique etait de 1,81 ±0,25 L/minute (IC 95 % 1,65-1,97) et le volume de distribution de 4,15±0,86 L/kg (IC 95 % 3,71). CONCLUSION: L'analgesie et les effets non analgesiques semblent correler avec les concentrations plasmatiques de l'hydromorphone.

Concentration‐Effect Relationship after Intravenous Hydromorphone Administration: Use of An Effect Compartment Model and System Analysis to Minimize Hysteresis of Effects

“…The mean pupil size and mean saliva production were significantly reduced for up to 6 h after drug infusion. Details of the described analgesic and nonanalgesic effects have been given previously (12).…”

“…Details of the subjects, measurements, procedure and pharmacokinetics have been given previously (12).…”

“…17, 3.17, 4.17, 5.17, 6.17, 8.17, 11.17, 14.17, 24.17, 30.17, 48.17 and 72.17 h after the start of the infusion. Plasma samples were prepared and assayed for hydromorphone by high performance liquid chromatography (12).…”

“…The analgesic effect of opioids is difficult to quantify and compare between individual subjects, whereas in healthy subjects, experimental pain lacks the emotional components of clinical pain. Unlike analgesia, side effects of opioids, such as miosis and decrease of saliva production, can be measured accurately (9)(10)(11)(12). The E max model (13,14) was applied after administration of morphine to healthy subjects (9,11), where these nonanalgesic effects were shown to be related to estimated effect compartment concentrations.…”

“…Previously reported analgesic and nonanalgesic effects after intravenous administration of hydromorphone to 12 healthy volunteers appeared to be related to plasma concentrations of the drug (12). The effect variables comprised analgesia, studied as pressure pain thresholds (PPTs), and nonanalgesic effects of hydromorphone, measured as miosis and saliva production.…”