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206 A LAWSON

Opioid and non-opioid analgesics in the ICU


Opioid analgesics Alfentanil is a phenylpiperidine synthetic opioid. It has
Opioid analgesic drugs remain the mainstay of pain relief in similar pharmacodynamic properties to the other newer
the Critical Care Unit. Abnormal GI function in the critically opioids, but it shows considerable variability in its pharma-
sick consequently makes enteral administration undesirable. cokinetic profile from patient to patient. Interindividual
IV administration remains the mainstay. Pharmacokinetic variability in alfentanil clearance is likely to result from
considerations consequent upon organ dysfunction leading differences in hepatic P450-3A4 expression and to P450-
to altered absorption, distribution and metabolism usually 3A4-related drug interactions.
play the most important role in the choice of agent. Remifentanil has an extremely short context-sensitive half-
Most analgesics used on the ICU are metabolized via phase life and is independent of hepatic and renal function . In the
I or II pathways, and they are generally effectively metabo- cardiac- and neuro-ICU setting, remifentanil’s short half-life
lized in all but those with severe liver dysfunction. is especially desirable. It allows good neurological assess-
Metabolism is generally affected by liver blood flow rather ment when required, profound haemodynamic stability and
than hepatocyte function. Opioids exert their analgesic early extubation after bypass surgery. One study suggests
action by binding to the opioid receptors at both spinal that the intraoperative use might even reduce the need for a
and supraspinal sites. Unwanted effects include bradycar- post-operative ICU stay after major abdominal surgery.
dia, miosis, hypothermia, nausea, urinary retention, respira- Table 13.1.1 outlines commonly use regimes for opioid
tory depression and constipation. infusion in Critical Care Units.
Route of administration
The IV route is the most reliable way of delivering opioids Table 13.1.1 Infusion rates for commonly used opioids in
in the critically ill. Extradural opioids have been used, often critical care
in combination with local anaesthetics; inhalational and
Drug MEAC ng/ml t1/2 terminal (min) Dose mcg/kg/h
transmucosal opioids are only rarely used. Patient-controlled
modes of administration require a fully conscious and Alfentanil 50–100 90 30–60
orientated patient, and are therefore only of limited value Fentanyl 1–3 185 1–5
in the CCU. Sufentanil 0.2–0.5 160–210 0.2–1.0
Choice of drug Remifentanil n/a 10–20 30–60
The most commonly used opioids are morphine, fentanyl, Morphine 10–30 100–180 50–100
alfentanil and remifentanil
MEAC = minimally effective analgesic concentration.
Morphine
Morphine is the most often prescribed agent because of its
low cost, excellent analgesic efficacy and euphoric effects. It Non-opioid analgesics
has a peak effect within 20min, and duration of action Non-steroidal anti-inflammatory drugs (NSAIDs)
between 2 and 7h. It has low lipid solubility and volume of NSAIDs have opioid-sparing effects and have both central
distribution, and its duration of action is determined by and peripheral sites of analgesic activity. The use in the criti-
hepatic metabolism. It is metabolized by the liver to the cally ill is however controversial. Their metabolism and
water-soluble morphine-6-glucuronide and morphine- excretion is dependent on liver and kidney function, both of
3-glucuronide, which are then renally excreted. Morphine- which pathways are frequently impaired in the ICU patient.
6-glucuronide is 2–800 times analgesically more potent than NSAIDs decrease the prostaglandin-dependent renal blood
morphine and accumulates in renal dysfunction. This can lead flow and are associated with an increased gastric ulceration
to unwanted prolonged sedation and respiratory depression risk. It seems prudent to avoid this class in the critically ill in
Morphine-3-glucuronide is not analgesically active. the absence of any definite gain to be had.
Fentanyl, alfentanil and remifentanil A new class of agents has been developed that selectively
Fentanyl is a synthetic opioid; it is the preferred analgesic inhibit the inducible cyclo-oxygenase enzyme, COX-2.
agent for critically ill patients with haemodynamic instabil- By sparing physiological tissue prostaglandin production
ity and for patients manifesting symptoms of histamine while inhibiting the COX-2-related inflammatory processes,
release with morphine or morphine allergy. Fentanyl is these agents are thought to offer the potential of effective
50–100 times more potent than morphine; it has extremely analgesia with fewer side effects than previous NSAIDs.
low bioavailability and therefore can be given by any route They have been shown to be as effective as NSAIDs in the
other than the GI tract. It is extremely lipid soluble and has management of post-operative analgesia. Adverse effects
an onset of action within 30s, with a peak effect in 5–15min. on renal blood flow, which are similar those of to conven-
It has a short half-life of 30–60min following redistribution, tional NSAIDs, and concerns regarding potential prothrom-
but accumulation in peripheral compartments can increase botic effects of at least some of the COX-2 agents, will limit
the half-life to 9–16h. their use in the critically ill patient.
Fentanyl is metabolized in the liver to pharmacologically Ketamine
inactive metabolites, which are renally excreted. In criti- This IV anaesthetic agent has intense analgesic properties
cally ill patients with renal failure there is an increase in the even at subanaesthetic levels, maintaining the airway,
volume of distribution and half-life of fentanyl. Fentanyl has and has stimulatory effects on the respiratory and cardio-
minimal cardiovascular effects compared with morphine. vascular system. It is used in specific painful proce-
Following a long infusion of fentanyl, accumulation may dures, particularly in burn patients for dressing changes.
cause prolonged respiratory depression.
CHAPTER 13.1 Opioid and non-opioid analgesics in the ICU 207

Hallucinations and emergence phenomena can be attenu- stimulation (TENS), acupuncture, aromatherapy, etc., should
ated by the co-administration of benzodiazepines. not be withheld. Anecdotal evidence suggests a benefit
There is furthermore some evidence, that ketamine can be from acupuncture in neuropathic pain, and reduced seda-
useful in chronic pain states such as central pain, complex tive and analgesic requirements following aromatherapy.
regional pain syndrome, fibromyalgia and neuropathic pain. Summary
Either alone or in combination with opioids it provides
Opioids are the most commonly used analgesic agents,
rapid, effective and prolonged analgesia .
often giving in combination with sedative drugs. There is no
Neuropathic pain agents doubt that this method is effective and cheap, and staff have
Some patients may be suffering from or develop neuro- a wealth of experience in its use. However, such regimes do
pathic pain. This sort of pain may be difficult to manage not provide satisfactory pain relief in all patients.
with standard analgesics, and consideration should be given What is needed to avoid patients experiencing pain while
to adding in specific drugs for neuropathic pain as outlined in Ithe CU is individualized, goal-directed analgesic regimes
in Table 13.1.2. Patients may also have pre-existing neuro- in their own right, not as a side effect of sedation. In con-
pathic pain problems; medication should be continued cert with analgesia, anxiety, the physical environment and
where possible. the patient’s sleeping pattern need to be considered.
Adherence to a clear protocol may be as important as
Table 13.1.2 Adjuvant therapies for pain in critical care. choice of medication.
Further reading
Drug Dose mg Neuropathic Sleep PTSD Barr J, Donner A. Optimal intravenous dosing strategies for seda-
pain tives and analgesics in the intensive care unit. Crit Care Clin 1995;
11: 827–47.
Tricyclic 20–100 nocte + ++ +
antidepressants Breen D, Karabinis A, Malbrain M, et al. Decreased duration of
mechanical ventilation when comparing analgesia-based sedation
Gabapentin 100–900 ++ + +? using remifentanil with standard hypnotic-based sedation for up
Pregabalin 25–300 ++ + +? to 10 days in intensive care unit patients: a randomised trial. Crit
Care. 2005; 9: R200–10.
PTSD = post-traumatic stress disorder. Curtis SP, Ng J, Yu Q, et al. Renal effects of etoricoxib and comparator
nonsteroidal anti-inflammatory drugs in controlled clinical trials.
Clin Ther 2004; 26: 70–83.
Adjuvant therapies Kuhlen R, Putensen C. Remifentanil for analgesia-based sedation in
Especially in patients with features of chronic pain or the intensive care unit. Crit Care 2004; 8: 13–4.
altered sleep patterns, tricyclic antidepressants have been Muellejans B, Matthey T, Scholpp J, et al. Sedation in the intensive
used extensively. There might be a rationale for using these care unit with remifentanil/propofol versus midazolam/fentanyl:
drugs in the medium- to long-stay patient where a constel- a randomised, open-label, pharmacoeconomic trial. Crit Care
lation of pain, anxiety and depression co-exists, possibly 2006; 10: R91.
along with a disturbed sleep pattern. There is evidence that Roemsing J, Moeniche S. A systematic review of COX-2 inhibitors
the usage of tricyclics, and possibly some of the drugs used compared with traditional NSAIDs, or different COX-2 inhibitors
to treat neuropathic pain, may reduce the development of for post-opereative pain. Acta Anaesthesiol Scand 2004; 48: 525–46.
post-traumatic stress disorder (PTSD) in ICU survivors. Wilson W, Smedira N, Fink C, et al. Ordering and administration of
sedatives and analgesics during the withholding and withdrawal of
Alternative therapies life support from critically ill patients. JAMA 1992; 267: 949–53.
No evidence exits to support the use of alternative thera- http://www.anzca.edu.au/publications/acutepain.
pies in the critically ill. In the absence of any untoward htm
effects, however, the use of transcutaneous electrical nerve

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