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Published on 1 November 2007

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Clinical pharmacists focus on pain at Istanbul symposium

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Laurence A Goldberg
FRPharmS

Editorial Consultant
HPE

E: lag@salt.u-net.com

Chronic pain affects about 20% of people in the world and has a significant social impact. Absence from work due to pain is estimated to cost European economies €34 bn per year, according to Aygin Bayraktar (Hacettepe ­University, Ankara, Turkey).

In Europe, chronic pain affects 70 million people and, on average, it lasts for seven years. In one survey of more than 46,000 people, a quarter said that pain affected their career, about 20% were depressed and about 20% had lost their jobs because of their pain. When questioned about pain treatment, 40% did not have adequate pain control and 28% did not believe that their doctors knew how to control their pain.

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is an individual and multifactorial experience that is influenced by culture, previous pain, beliefs, mood and ability to cope, said Dr Bayraktar.

Acute pain is usually a symptom of injury or disease whereas chronic pain is considered by some to be a disease in its own right. It is not always easy to separate acute and chronic pain, she added. The characteristics of acute pain are that it is of rapid onset, usually of limited duration and has an obvious link to injury or acute illness. In addition, it has a protective purpose, is self-limiting but can become chronic if left untreated. Acute pain can be the result of trauma, surgery or childbirth. Chronic pain is usually of insidious or gradual onset and commonly persists beyond the time of healing of an injury. It depresses and debilitates the sufferer and it is often difficult to identify the cause. Chronic pain syndromes include chronic low back pain, myofascial pain, headache and phantom limb pain.

Good pain management depends on appropriate assessment, monitoring and documentation, said Dr Bayraktar. However, the situation is complicated by a number of factors. These include fear of opioid addiction, irrational selection of opioids, inadequate understanding of the pharmacokinetics and pharmacodynamics of opioids, lack of knowledge about the patient’s perceptions of pain and illness and lack of information about other techniques for pain ­management. The range of measure available for the management of pain is summarised in Table 1.

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Acute pain
The pharmacological management of pain should be based on the three-step WHO pain relief ladder and treatment should be modified according to the patient’s needs, explained Dr Bayraktar. For acute pain, for example, post-operative pain, treatment should start at the top of the ladder with strong opioids and regional analgesia and descend through mild opioids to non-opioid analgesics.

NSAIDs, cox-2 inhibitors (coxibs) and paracetamol are used orally for mild to moderate pain. They can also be given rectally or topically if required for post-operative pain. The only available intravenous drugs in this group are ketorolac and propacetamol, noted Dr Bayraktar. Parenteral and rectal forms are as effective as oral doses but give rise to similar numbers of side-effects, she added.

An advantage of using NSAIDs and coxibs for postoperative pain relief is that they can lead to about 30–40% reduction in opioid use. The American Society of Anesthesiologists has recommended that, “unless contraindicated, all patients should receive a round-the-clock regimen of NSAIDs, coxibs, or acetaminophen (paracetamol) in the peri-operative setting” (see Resources).

A meta-analysis of trials of paracetamol for post-operative pain (see Resources) concluded that there was a morphine-sparing effect of 20% over the first 24 hours, but there was no reduction in the incidence of morphine-related adverse events. Moreover, paracetamol might be an alternative to NSAIDs in high-risk patients and it could be combined with NSAIDs or coxibs. A separate study examining the use of NSAIDs, coxibs and paracetamol with patient-controlled analgesia concluded that use of NSAIDs, but not coxibs or paracetamol, decreased the incidence of post-operative nausea and vomiting (PONV) and sedation. However, when coxibs were used after orthopaedic surgery there was improved analgesia, shorter hospitalisation times, improved recovery and function and reduced healthcare costs.

Turning to opioids, Dr Bayraktar pointed out that the efficacy of “weak” opioids, such as codeine and dextropropoxyphene, was not always proven and the benefits were unclear.

Strong opioids such as morphine, oxycodone and fentanyl are used for moderate-severe post-operative pain, with or without simple/non-opioid analgesics. They may be given orally, intravenously (as patient-controlled analgesia) or subcutaneously. In addition, transdermal fentanyl is suitable for patients with renal impairment and the intrathecal or epidural routes of administration can provide sustained analgesia.

Partial agonists such as buprenorphine and ­tramadol have similar efficacy but may cause fewer gastrointestinal, respiratory and urinary side-effects. ­Tramadol is said to be useful in patients with poor cardiopulmonary function in whom NSAIDs are not recommended or need to be used with caution. These include elderly patients, obese patients, smokers and people with impaired hepatic or renal function. Both parenteral and oral forms are effective and well tolerated in the perioperative setting, said Dr Bayraktar.

Patient-controlled analgesia, when compared to intravenous or subcutaneous opioid administration, does not reduce opioid consumption, but the quality of analgesia is sometimes better and patient satisfaction is almost always higher.Opioids offer the advantage of flexibility in dosing but there are still problems in the effective use of opioids for acute pain particularly because the use of “as-needed” prescriptions is still far too common.

Other measures that are sometimes used for acute pain management include the use of local anaesthetics for wound infiltration or regional nerve blocks, the use of adjuvants such as NMDA antagonists, alpha-2 agonists, anticonvulsants and anti­depressants.

Chronic pain
A multimodal approach involving analgesics, therapy for the underlying disease (such as surgery, radiation, chemotherapy) and complementary treatments is used for the management of chronic pain, said Dr Bayraktar. It is estimated that NSAIDs are used to treat 44% of cases of chronic pain.

Antidepressants have a role in the treatment of chronic pain. Antidepressants have long been the treatment of choice for neuropathic pain and there have been favourable results in arthritis, fibro­myalgia, headache and low back pain. Tricyclic anti­depressants (TCAs) such as amitriptyline, desipramine or ­notriptyline are the first-choice agents. Selective serotonin reuptake inhibitors (SSRIs) appear to be much less effective, added Dr Bayraktar.

Amitriptyline is the best documented of the available agents. It should be taken at night to minimise side-effects. Desipramine and notriptyline have fewer side-effects and can be taken during the day. Common TCA side-effects include cardiovascular abnormalities, balance problems and cognitive impairment. Treatment should be started with low doses.

Some anticonvulsants are licensed for the treatment of various types of nerve-related pain; for example, ­carbamazepine is licensed for trigeminal neuralgia and pregabalin is licensed for post-herpetic neuralgia (PHN). Gabapentin is effective in diabetic polyneuropathies, PHN, phantom limb pain and spinal cord injury. However, carbamazepine and TCAs are also effective in these conditions and are cheaper alternatives. Gabapentin has minimal side-effects, is not metabolised and has no interactions. Furthermore, it is the only drug that is indicated for neuropathic pain. Again, treatment should start with a low dose and be increased every 1–7 days.

Clonazepam might have a role here – it has a low rate of adverse events and is easy to dose – but it is a benzodiazepine and so the risk of tolerance has to be considered.

Opioids can be considered for chronic pain after there has been an adequate trial of paracetamol or NSAIDs for nociceptive pain, or TCAs or anticonvulsants for neuropathic pain. Strong opioids are more effective than NSAIDs or TCAs for pain relief, but not for improving functional outcomes. Treatment should be started with immediate-release dosage forms and only when the desired degree of pain relief has been achieved should a slow-release product be introduced.

Weak opioids such as codeine or tramadol should be tried in the first instance, recommended Dr Bayraktar. Tramadol is effective for neuropathic and musculoskeletal pain and has similar efficacy to codeine. The most common adverse effects are headaches, nausea and dizziness. It causes less constipation and is associated with a lower risk of respiratory depression than other opioids. However, it can cause seizures. when taken in overdose or in combination with serotonergic medications.

Strong opioids such as oxycodone, ­hydromorphone and morphine are suitable second-line agents. ­Oxycodone and hydromorphone are less likely to cause sedation in the elderly than morphine, but should be used with caution in anyone who has a current or past history of addiction. Morphine has active metabolites that can accumulate to toxic levels in patients with renal dysfunction.

Morphine should be given orally if at all possible, said Dr Bayraktar. The duration of action will be 3–6 hours. Slow-release morphine preparations are available that will prolong the action to 8–12 hours or 12–24 hours. Fentanyl patches will last for 48–72 hours. A useful feature of some of the morphine preparations (such as MXL® capsules) is that the capsules can be opened and the slow-release granules can be sprinkled on food, providing they are not chewed. This is particularly good for patients who have difficulty swallowing or who have nasogastric tubes in place.

Third-line options include fentanyl (transdermal) and methadone. Fentanyl patches should be used only for patients who are taking the equivalent of 90–100 mg/day morphine and who are fully tolerant to this dose. They should be reserved for patients whose pain cannot be controlled with oral opioids, those who are unable to swallow or who have gastro-intestinal dysfunction. Other groups who are suitable for fentanyl analgesia are those who are intolerant of other opioids due to allergy or adverse drug events and those with concurrent cardiac and renal disease. Methadone is the agent of first choice in patients with chronic pain and opioid dependence. It is also an option for patients with severe organic pain, particularly neuropathic pain when all other opioids have failed.

In conclusion, Dr Bayraktar pointed out that there is little long-term organ toxicity with opioids and that as a class of medicines they are safer than NSAIDs. Moreover, they have few effects on cognitive functioning, at stable moderate doses. Fatigue, constipation and nausea are common problems, there is a risk of long-term hyperalgesia with chronic therapy and erectile dysfunction can be a problem with high doses.

Resources
ASATFAPM. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2004;100:1573-81.

Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery:
meta-analysis of randomized controlled trials. Br J Anaesth 2005;4:505-13.



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