Implications Of Agonistantagonists In Postoperative Pain Management

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While it had been demonstrated that this group of opioids when being used for postoperative pain management result in a lesser incidence of postoperative nausea and/or emesis (Figure III-56), from the clinical point of view it is important to note, that one should never mix a pure ^-type ligand such as morphine or hydrocodone with an agonist/antagonist such as pentazocine, nalbuphine or butorphanol.

This is because the latter agents induce an antagonistic effect at the opioid ^-receptor while they mediate their analgesic effect through interaction with the opioid K-receptor (Figure III-57). Therefore, an agonist/antagonist given after a pure ^-type ligand is able to reverse analgesia resulting in an increase of pain [173].

It is because of this antagonistic potency that some mixed agonist/antagonists such as nalbuphine and butorphanol (Table III-17) can be used as reversal agents in an overhang of fentanyl-related respiratory depression [174, 175, 176]. At the same time these agents have a lesser spastic effect on the sphincter Oddi resulting in more favorable intrabiliary tract dynamics [177]. Last but not least, they have a lesser addiction liability, which is why they are scheduled as class IV agents, and not like morphine, need a special opiate prescription form.

Nalbuphine Piritramide Morphine Pethidine

Figure 111-56. Incidence of nausea and vomiting in patients receiving different opioids for postoperative pain management, using either nalbuphine (1086 patients), pethidine (234 patients), morphine (486 patients) and the fentanyl analogue piritramide (9756 patients) (Adapted from [171, 172])

Nalbuphine Piritramide Morphine Pethidine

Figure 111-56. Incidence of nausea and vomiting in patients receiving different opioids for postoperative pain management, using either nalbuphine (1086 patients), pethidine (234 patients), morphine (486 patients) and the fentanyl analogue piritramide (9756 patients) (Adapted from [171, 172])

Table III-17. Agonistic and antagonistic potency of various opioid agonist/antagonists and partial agonists, when compared to the pure agonist morphine (= 1) and the pure antagonist naloxone (= 1) respectively

Opioid

Company

Antagoniste profile

Agonistic profile

Analgesia ceiling (mg/70 kg)

Butorphanol

BristolMeyers

0.025

40

> 1.2

Buprenorphine

Reckitt Benckiser

0.5

30

2-4

Levallorphane

Roche

0.2

1

?

Naloxone

Watson

1

0

0

Morphine

Astra/Zeneca

0

1

0

Nalbuphine

Endo/Du Pont

0.5

0.8

240

Pentazocine

Watson

0.04

0.4

90

Meptazinol

Shire

0.02

0.15

100

In addition this group of opioids is characterized by a respiratory ceiling effect. In comparison to morphine, cumulative dosages do not result in a dose-dependant impairment of respiratory drive until total apnea. On the contrary, every agonist/antagonist has a specific dose where respiratory depression reaches a plateau, "the ceiling". Further increase in dosages even results in a reversal of respiratory impairment (Figure III-58).

However, similar to a respiratory "ceiling effect" there is also an analgesic ceiling effect [179, 180]. Depending on the product and the dose being administered there is no further increase in analgesia (Table III-18). It is because of this analgsic

Receptors

Effect

Antag. Agon.

Supraspinal Analgesia Respiratory Depression Euphoria Addiction Liability Vasomotor Blockade Miosis

Nalbuphine 0 ^ 1

Fentanyl

Miosis

Sedation

Nalbuphine 0 1

Figure III-57. Principal of mode of action of agonist/antagonists with an antagonistic effect at the and the mediation of analgesia via the opioid K-site

Figure III-57. Principal of mode of action of agonist/antagonists with an antagonistic effect at the and the mediation of analgesia via the opioid K-site

Lambda Messger

Figure III-58. Increasing doses of morphine result in a continuous impairment of respiratory drive. Contrary, increasing doses of the mixed agonist/antagonist analgesic nalbuphine, at a certain quantity, result in a "ceiling effect" where there is no further deterioration of respiration Adapted from [178]

Figure III-58. Increasing doses of morphine result in a continuous impairment of respiratory drive. Contrary, increasing doses of the mixed agonist/antagonist analgesic nalbuphine, at a certain quantity, result in a "ceiling effect" where there is no further deterioration of respiration Adapted from [178]

"ceiling effect" that very intense postoperative pain is insufficiently treated with mixed narcotic analgesics.

The mixed narcotic agonist/antagonist butorphanol has been recommended for nasal application as a useful agent to block postoperative pain. Aside from its use as an "on-demand" type of spray by the patient, and similar to all other K-ligands characterized by marked sedative effect, it was claimed to result in a reduced incidence of other side effects [181]. Due to the fast reabsorption via nasal soft tissue (high lipophilicity), there is an onset time within minutes with peak plasma levels after 1 h. It is because of this first-pass transfer that the liver is by-passed, resulting in an up to 70% bioavailability. Also, because of the bypass of the liver, lower doses than usual are needed, which is the cause of lesser

Table III-18. Suggested dosing of opioids in patient-controlled analgesia (PCA) and their respective lock-out times

Opioid

Bolus on-demand dose

Lockout time (min)

Morphine

1-2 mg

8-15

Buprenorphine

1 |g

30

Fentanyl

20-40 |ig

5-8

Modified from [195]

Modified from [195]

side effects. With a mean duration of action between 4 and 5h, the agent was able to induce sufficient to good pain relief in medium to intense nociception following orthopedic procedures, cesarian section, hernia repair [181,182] or in post episiotomy pain [183]. It should be noted that there is little or no irritation of nasal soft tissue even after prolonged use [184]. The nasal preparation of butorphanol (StadolĀ® NS) has also been tested positive in migraine headache and/or cluster pain [185, 186]

In comparison to the mixed narcotic analgesics, the partial agonist meptazinol has an interesting pharmacodynamic profile. With an analgesic potency, similarly to that of pethidine (meperidine, USP), when given in equipotent dosages (100mg/70kg) it does have a lesser respiratory depressive and a lesser sedative effect than penta-zocine (60 mg/70 kg) or pethidine (100 mg/70 kg). Especially in obstetrics, when any agent given for the alleviation of pain should not affect the neonate, it has a larger margin of safety resulting in higher APGAR-scores when compared to pethidine [187]. And when compared with morphine in the management of postoperative pain, it resulted in a lesser impairment of respiration [188]. This drug therefore should be considered as a true alternative especially in obstetrics but also in the aging patient population with a frail cardiovascular system, who because of preexisting respiratory problems is more sensitive in developing an opioid-related respiratory impairment.

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