Figure 111-51. Postoperative pain therapy and the corresponding plasma levels, using time-contingent dosing. The goal is an overlap of a descending opioid plasma level resulting in sufficient receptor occupation instance an opioid like sufentanil, although being the most powerful agent available, it however results in severe respiratory depression. Other opioids such as fentanyl or alfentanil have a too short half-life of only 20-30 min and 5-10 min respectively. Pethidine, although having a much longer duration of action and shows a lesser incidence of respiratory depression, has a mean duration of action between 2 and 3 h. However, because of its cardio-depressive effects and especially its tachyarrhythmic potency this is accompanied by an increase in myocardial oxygen consumption (MVO2). It, therefore, is not considered the optimal agent for postoperative pain management. Although not having the most advantageous profile, some of the standard opioids in this regard, i.e. morphine and/or hydromorphone do have a number of advantages when being used in the postoperative period. First of all the duration of action is between 3 and 5 h and when being used in the lower dose range, they do not induce a clinically relevant impairment of respiration. Due to the histamine liberating effect of morphine, sometimes a relevant drop in blood pressure is encountered, especially in patients, who due to an excessive intraoperative blood loss already have a compromised circulation. While codeine has a similar duration as pethidine, it may be a favorable agent postoperatively in infants and young children [160, 161]. In this respect, also tramadol, because of its negligible respiratory depression and not being a scheduled type opioid, is an analgesic for use in pediatrics but also after minor surgical procedures [162]. The opioid with the longest duration of action of up to 10h is buprenorphine [163, 164], which has a sufficient potency (40 times morphine) to combat severe postoperative pain after large surgical interventions (Figure III-52).

When using buprenorphine one has to realize that its onset of action is fast within 2-5 min, however its full effect will be seen after a period of 45 min. This is because the agent has a very slow association characteristic before it is fully bound to the opioid receptor [165]. It is therefore mandatory not to administer a







0 2

' 4 r 6 ' 8

Figure 111-52. Mean duration of action (hours) of various opioids for use in the postoperative time period

Figure 111-52. Mean duration of action (hours) of various opioids for use in the postoperative time period second injection or give another buccal tablet within this time frame in order not to induce an overdose with all the sequelae of any excessive opioid intake (i.e., respiratory impairment). This especially has to be recognized in the elderly patient because he is more sensitive to develop an insufficient respiratory drive. Although a selective antagonist such as naloxone can easily antagonize such event, one has to realize that higher dosages (1-2mg/70kg body weight) than normal may become necessary in order to displace buprenorphine from its receptor. If an antagonist is not available, also a non-specific analeptic such as doxapram (Dopram®) can be used because it stimulates respiratory drive via activation of chemoreceptors at the glomus caroticus, which in turn activates the respiratory center. At the same time it also affects blood pressure via pressor receptors in the aortic arch (Figure III-53). In addition almitrine (Vectarion®), another non-specifc analeptic can be used, which has similar properties as doxapram. Aminophenazole (Pamadine®) directly stimulates the medullary respiratory center and the agent physostigmine induces

Figure III-53. Mode of action of the analeptic agent doxapram resulting in a nonspecific activation of respiratory drive

an overall decrease in acetylcholine (ACh) turnover, specifically in the medulla, counteracting opioid-induced reduction of ACh-release.

Especially after ambulatory surgery the patient needs some back-up agent, which is sufficiently potent for pain alleviation, however, at the same time does not compromise the cardiovascular or the respiratory system. Since those patients usually have undergone minor surgical procedures, often a peripheral NSAID is sufficient for pain therapy especially if the patient uses the analgesic as a self-medication. However, sometimes an opioid becomes as necessary as the pain becomes intense. Preliminary results with a time-controlled release formulation of dihydrocodeine seem to be promising. This agent not only results in a time-contingent long duration of action after minor surgical procedures such as endoscopic cholecystectomy and/or arthroscopy [166, 167]. When given together with a peripheral NSAID it results in good to optimal pain relief. While its time to max efficacy is between 2 and 3h, its duration is between 8 and 12 h; it therefore can be used for acute treatment of exacerbating pain without the potential risk of respiratory depression.

In combating postoperative pain, a three-step ladder is proposed, where according to the intensity of individual pain, the proper analgesic can be chosen (Figure III-54).

Type of analgesia


Special analgesia with an epidural opioid + local anesthetic (lumbar, thoracic)

Fentanyl, Morphine Clonidine, Sufentanil

Persistent/increasing pain

Special analgesia with opioid + non-opioid analgesic +PCA

Tramadol, Morphine, Hydrocodone, Meptazinol, Buprenorphine

Persistentr/increasing pain

Acetaminophen, Paracetamol, ASS, Ibuprofen, infiltration, installation

Basic analgesia with non-opioid analgesics, Regional analgesia of Periphereral nerves

Figure III-54. A three-step ladder in modern postoperative pain management using a multimodal approach

In summary, the following management options are available for post-operative pain management (Table III-16).

Pharmacologic management of mild to moderate postoperative pain should begin, unless there is a contraindication, with an NSAID. However, moderately severe to severe pain should normally be treated initially with an opioid analgesic, with or without an NSAID.

Even when insufficient alone to control pain, NSAIDs, including acetaminophen, have significant opioid dose-sparing effects on postoperative pain and hence can be useful in reducing opioid side effects. If the patient cannot tolerate oral medication, alternative routes such as rectal administration can be used. At present, one NSAID (ketorolac) is approved by the Food and Drug Administration for parenteral use. NSAIDs must be used with care in patients with thrombocytopenia or coagu-lopathies and in patients who are at risk for bleeding or gastric ulceration. However, acetaminophen does not affect platelet function, and some evidence exists that two salicylates (salsalate and choline magnesium trisalicylate) do not profoundly affect platelet aggregation.

Opioid analgesics are the cornerstone for management of moderate to severe acute pain. Effective use of these agents facilitates postoperative activities such as coughing, deep breathing exercises, ambulation, and physical therapy. When pain cannot be adequately controlled despite increasing the opioid dose, a prompt search for residual operative pathology is indicated, and other diagnoses such as neuropathic pain should be considered. Opioid tolerance and physiologic dependence are unusual in short-term postoperative use in opioid naive patients. Likewise, psychologic dependence and addiction are extremely unlikely to develop after the use of opioids for acute pain.

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