ally diagnosed cerebrovascular disorders or heart diseases (NYHA II-IV). The risk of an acute renal failure is similar to when administering NSAID.

Selective cyclooxygenasis-2-inhibitors are not approved for persons under 18 years of age.

Parecoxib: Approved for the short-term treatment (48 hours) of post-surgical pain. Recommended dosage is 40 mg and it is administered intravenously or intramuscularly. After a period of 12 hours, another 20 mg or 40 mg can be administered again. There are no special dosage recommendations for older patients. Due to the missing effect on the thrombocyte function, parecoxib is suitable for pain management after skin grafting or debridement.

Celecoxib: Administered orally, daily dosage 200 mg in 1 or 2 single doses.

Opioids (Table 2)

Opioids are the fundamental substances in pain management of severe burn injuries. Due to their various possibilities of application, opioids are suitable for all stages of the treatment.

Apart from the typical side effects as for example depressed breathing, bradycardia, obstipation, nausea and itching, the following facts have to be considered:

After a short time of administration, opioids induce adaptation mechanisms and cause the development of functional antagonisms, which might lead to an opioid tolerance or an opioidinduced hyperalgesia [34, 35]. Whereas in an opioid tolerance the dosage of the analgesic has to be increased to have the same effect, in an opi- oid-induced hyperalgesia the sensation of pain is stronger. Although both phenomena have different pathophysiologic mechanisms, the activation of NMDA-receptors plays a key role in both cases [36–38]. It is recommended to combine opioids with NMDA-receptor antagonists.

Liver and renal disorders cause an alteration of the pharmacokinetics of opioids. In the presence of liver insufficiency an increased bio-availability of morphine, hydromorphone and pethidine through reduction of the first-pass-metabolism has to be anticipated.

Table 2. Pharmacological data of opioids

* Max. Daily dosage: 400 mg–600 mg

rA renal insufficiency can cause the onset of active metabolites, e. g.:

rMorphine-6-glukuronid: little analgesic but significant sedating effect

rMorphine-3-glukuronid: pronociceptive, excitatoric effect [39]. A cumulation can be coresponsible for the development of an opioid tolerance [34].

rNorpethidine: neurotoxic effect

Thus the administration of opioids should always be embedded in a multimodal treatment. Due to different metabolites and different response rates to the opioid receptors, the opioid rotation is an important option. To administer the correct quantity during a change of opioids it is recommended to start with 50% of the calculated equivalence dosage of the new opioid to be able to titrate as needed. This procedure is reasonable since the present equivalence tables are suited only for opioid naïve patients and due to a tolerance development the dosage equivalence varies greatly.

The genetic polymorphism with multiple isoforms for the μ-, -, and -receptors is the reason why the effects of opioids can interindividually be very different. Thus the dosage must be determined individually. In older or weak patients the initial dosage should be reduced and the effect of the initial dosage should be taken into consideration when further dosages are determined.

Any opioid-caused effect can be reversed immediately and entirely by administering a specific antagonist as for example Naloxon.

are weaker. However, there is a higher incidence of vomiting and nausea. Due to genetic polymorphisms in the cytochrome oxydase system the analgesic effect of Tramadol is limited in some patients (appr. 10% in Caucasians) [40].

Tramadol is also effective in the treatment of neuropathic pain [41]. Neuropathic pain might play a role in chronic pain after burn trauma (see III. Pathophysiology of pain after burn injuries/3. Neuropathic pain). However, the current literature does not provide any evaluation of the effects of Tramadol on neuropathic pain in burn patients.

Pethidine

Although pethidine is slowly but steadily replaced by more modern preparations in numerous European countries, it still remains one of the most important analgesic medication throughout the world. Pethidine is a μ-receptor agonist with a 0.1–0.2 fold analgesic potence of morphine. Onset of action takes place after 5 minutes and lasts for 2 to 3 hours. During degradation the active neurotoxic metabolite norpethidine is produced which, when acculmulated, can cause convulsion and myoclonus. Thus pethidine is suitable for intravenous administration in acute cases but not as continuous treatment. Pethidine reduces the post operative shivering better than morphine. In addition it shows the least spasmogenicity of all opioids. Currently it is particularly used in the initial treatment of children with burn trauma.

Weak opioids

The daily dosage of weak opioids must be obeyed.

Tramadol

Tramadol is an analgesic with a combination of opi- oid-antagonistic effects and re-uptake inhibition of serotonine and noradrenaline. It is available either as delayed-action preparation or non-delayed action preparation. In addition it is available as parenterally injectable pharmacon. It is suitable for the therapy of acute and chronic pain. Compared to morphine and other opioids, Tramadol’s breathing depressing effect and its inhibition of the gastro-intestinal tract

Strong opioids

There is no clinically relevant maximum dosage for strong opioids.

Morphine

In pain management morphine is commonly used as reference opioid throughout the world. It can be administered orally or parenterally. Due to its high first-pass effect its bioavailability is only 20%–40%. When administered orally, the dosage needs to be 3-fold higher than when administered parenterally. Morphine is degraded in the liver to morphine-3- glucuronide (pronociceptive effect) and morphine-

6-glucuronide (sedating effect). These metabolites show a significantly higher elimination half-life (up to 72 hours) than morphine. In the presence of renal insufficiency both metabolites might accumulate. After intravenous administration the onset of maximum action takes place after 15 to 30 minutes. The action time of a single dosage is 3 to 5 hours. Possible side effects are a dosage-dependent respiratory depression and vasodilatoric effects as well as release of histamines with vasodilatation and bronchoconstriction.

Piritramide

Piritramide is a μ-receptor agonist with a relative activity of 0.7 compared to morphine. It is very well suitable in post-operative intravenous pain management, in the intensive care unit and as patient-con- trolled analgesic. The onset of action takes place after 5 to 10 minutes and generally lasts for 4 to 6 hours. The sedative components are stronger than those of morphine. Piritramide acts hardly euphorizing and its spasmogenicity is low.

Fentanyl

The potency of fentanyl is 100-fold higher than the potency of morphine (analgesic and side effects). A dosage of 100 μg equals approximately 10 mg morphine. It maintains the cardiac stability and has a high therapeutic index. Compared to morphine the histamine release remains low.

Forms of administration:

Intravenous: The onset of maximum action takes place after 4 to 5 minutes and the time of action is 20 to 30 minutes. Fentanyl is officially approved for intraoperative analgesia (with artificial respiration) and for analgosedation in the intensive care unit. However, fentanyl is more and more used in awake patients not receiving artificial respiration: a successful administration of fentanyl in combination with propofol for the analgosedation of non-intubated children (5 to 60 months, ASA II-III, TBSA 5%-25%) during dressing change after skin grafting has been described [42]. Linneman et al. have investigated the effect of fentanyl in 55 burn patients (9 months to 75 years) in a

retrospective study. 31% of the patients developed a transient respiratory depression. However, additional oxygen or intubation have not been necessary for any patient. With adequate monitoring and in the presence of an anesthetist the administration of fentanyl during dressing change is described as effective and secure [43].

Intravenous PCA: The patient-controlled analgesia with fentanyl during dressing change in burn patients is very effective. Signs of circulatory insufficiency or respiratory depression have not been described [44]. Recommended pump programming: bolus of 30 μg fentanyl with a lock-out time of 5 minutes after an initial loading dose of 1 μg/kg fentanyl.

Transdermal: Only suitable for chronic pain management and in the presence of adequate resorption areas. Onset of action takes place after 12 to 24 hours.

Oromucosal: Suitable in case of breakthrough pain despite of a permanent opioid therapy (see also breakthrough pain).

Hydromorphone

Hydromorphone is a μ-receptor agonist and its analgesic potency is 6 to 7.5-fold higher than the analgesic potency of morphine. It can be administered orally (non-retarded, retarded) and parenterally injectably. Hydromorphone shows a favorable pharmacological profile due to its lack of active metabolites and its low plasma protein binding (appr. 8%). Thus it is particularly suitable, also for permanent treatment, for patients suffering from renal insufficiency.

Oxycodone

Oxycodone acts at the μ-receptors and also at the - and -receptors. In case of decreasing analgesic effects of a permanent opioid treatment, the rotation to oxycodone may have positive effects. Apart from that, oxycodone has been described as particularly effective in neuropathic pain [45, 46].

It has a bioavailability of 70% to 87% and its analgesic potency is comparable to morphine. Metabolites of oxycodone are noroxycodone and oxymorphone, both showing only very low analgesic activity. The level of active metabolites in the blood is not sig-