Introduction

Pain is a subjective experience and the best way to evaluate the effects of treatment is to ask the patient. Pain is not an unambiguous concept, but several pain types with different mechanisms may occur simultaneously. Nociceptive pain due to activation of nociceptors in the periphery, the pain receptors, following injury to the tissue. The inflammatory pain type is sharp and triggered by even gentle movements. Another type of pain often radiating in nature is neurogenic or neuropathic pain. There is also a large portion of patients experiencing a pain of unknown origin that often varies in intensity and extent. Knowledge of pain components is important for the choice of treatment.

Pain signalling and nerve tracts

A number of biochemical processes occur in the injured area following tissue damage. There is release of bradykinin, potassium, histamine, serotonin, coagulation factors and others, as well as activation of prostaglandin synthesis which stimulates various receptors including the different transient receptor potential vanilloid receptor to the nerve tracts that transmit the pain to the spinal cord where it connects to an upward path to the thalamus. From there further activation of different brain centres for learning, experience of pain, anxiety and localization of pain is propagated. An important relay centre in this process is the limbic system. There is also a descending system from the brain to the spinal cord that can inhibit the incoming signals from the periphery. Endorphins and enkephalins, e.g. endogenous morphine-like molecules, can also attenuate the incoming signals to the central nervous system (CNS).

Peripherally acting agents such as non-steroidal anti-inflammatory drugs (NSAIDS) and acetaminophen, may reduce the synthesis of prostaglandins and thereby desensitize nociceptors for pain stimuli. These drugs may also inhibit the prostaglandin enhancing effect in the CNS. Thus, the so called peripheral acting analgesics indeed may have a dual action on pain.

Pharmacologic treatment of pain

No fundamentally new drug principles have appeared for the clinical treatment of pain during the last 100 years. However, the introduction of the Pain Ladder by WHO has led to structured treatment and acknowledged that opioid drugs are important tools for cancer sufferers. The WHO ladder remains the mainstay of cancer pain treatment. However, it is based more on expert opinions than on evidence-based medicine and today the aetiology of pain is recognised as the most important indicator for treatment choice. A careful analysis of different pain components is important for choosing the most beneficial pharmacological treatment. The strong, sharp and burning pain sensitive to movements must be acknowledged in cancer and be adequately managed to decrease the patient’s anxiety as well. NSAIDs are important in the treatment of inflammatory pain and combined with morphine, treatment of both peripheral and central components of pain can be successful.

Acetaminophen
Acetaminophen, paracetamol, is a mainstay in pain management for all pain as the drug has both analgesic and antipyretic properties, while the effect to decrease a swollen tissue, the peripheral anti-inflammatory effect, is very small, if any. The working mechanism of acetaminophen has only recently been elucidated with identification of inhibition of cyclooxygenase or block of the prostaglandin synthesis primarily in the CNS as being the most important. Acetaminophen has a short half-life of two hours. The agent probably has a ceiling effect and single doses of 15–20 mg/kg are not considered to provide better analgesic effect. A normal dose of acetaminophen produces mild analgesia and few side effects. Acetaminophen may cause serious liver damage with necrosis at doses greater than 10g to adults. In the body, a substance glutathione can reduce the toxic metabolites responsible for the damage, but in large doses, this protection is not sufficient.

Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs have analgesic, antipyretic and an anti-inflammatory effect that reduce oedema and swelling in the injured area. The effect is exerted by inhibition of prostaglandin synthesis by peripheral blockade of the enzyme cyclooxygenase. As discussed above, a central prostaglandin inhibition might at least be part of this analgesic effect. Prostaglandins play an important role in regulating a variety of physiological functions, and a blockade of this system entails, in addition to the positive effects on pain, there are a number of side effects as well. NSAIDs are dispensed like many other painkillers according to their analgesic duration and half-life. This does not apply to aspirin which has an irreversible binding to the enzyme cyclooxygenase and the effects and side effects persist until the enzyme is re-synthesized. The most serious side effects may be seen in the gastrointestinal tract, but the adverse events are also seen due to longer bleeding time, less kidney blood flow and asthma symptoms. Aspirin should not be given to young children since they cannot metabolize metabolite salicylic acid and they may be exposed to a larger risk for metabolic acidosis.

On the market there are now selective cyclooxygenase inhibitors, COX-2 inhibitors, which may result in a reduced risk of some of the adverse effects of traditional NSAIDs. As a whole, NSAIDs, because of the high incidence of adverse events, should only be reserved for patients with a clear inflammatory component of pain. A short-acting agent such as ibuprofen may be the appropriate first choice.

Strong opioids
Strong opioids from the morphine group of drugs are primarily intended for post-operative pain or pain from malignancy. Strong opioids act via opioid receptors in the CNS and activate descending inhibitory pain pathways in the spinal cord, reducing sensory inflow from the periphery. They also decrease activity in the limbic system that reduces the unpleasantness of nociceptive stimuli. Opioid control is found in many organs, which can lead to undesirable effects. For instance, undesirable effects on the gastrointestinal tract with delayed intestinal passage may result in constipation which can be prevented with a liquid laxative. Opioid treatment may also cause sedation, nausea and sometimes vomiting. These side effects are transient because of rapid tolerance development. All opioids depress the hypothalamic–pituitary axis with possible reduction of many hormones leading to a variety of symptoms. Strong opioids may involve the risk of respiratory depression and addiction. The risk of dependence may though not hinder adequate pain management.

Morphine is the gold standard drug when a strong opioid is needed although no large differences in clinical effects distinguish the various opioids. Morphine has an excellent anxiolytic effect, which may be valuable in many situations. The agent acts both as parent compound and through the metabolites morphine-3-glucuronide and morphine-6-glucuronide. These accumulate in renal failure and can cause serious side effects. One of the metabolites, morphine-6-glucuronide, has a strong analgesic action of its own. In manifest renal failure, morphine is not used because of the risk of myoclonic seizures and CNS effects. Dose requirements can vary greatly between patients and is why an individual dosing with subsequent quality assurance of effects is important. Oral morphine treatment in acute and cancer pain reduces the patient’s dependence on healthcare professionals, provides good opportunity for individualization, prolonged duration of action and less side effects. Long-acting morphine preparations may be an option in chronic pain with little fluctuation in intensity. The development of tolerance to the analgesic effect may sometimes occur.

Other opioids have been used in cases where morphine is contraindicated. Oxycodone has become popular recently because of its low concentration of active metabolites and the possibility to use it in renal failure patients. This is mostly clinical experience and no evidence is available from controlled clinical trials. Until recently, ketobemidone, an opioid agonist with similar efficacy and pharmacokinetic profile to morphine, was used for the same purpose. Opioids are also available in transdermal preparations (such as fentanyl) but with large difference in pharmacokinetics.

These have also found a prominent place in treatment of cancerassociated pain of longer duration. Further, in severe pain, opioids may be given by epidural or spinal administration to alleviate the worst symptoms of the suffering patient.

Combination of analgesics
Combination formulations of analgesics are usually avoided though the various components differ in mechanism of action, therefore, they are often not given in the full dose and the components often have different pharmacokinetic profiles. Upon repeated dosing, this means that a risk of overdosing of one component and under-dosing of the other may occur. The best compounded fixed drug combinations are those containing acetaminophen and the weak opioid codeine. Codeine is metabolized to provide about 10% by weight and has the same clinical effect and side effect profile as morphine.

New combinations of drugs targeting neuropathic pain are being tested, mostly based on gabapentin as primary compound.

Cannabinoids, alpha-2-adrenergics, nicotine, lidocaine and ketamine all represent drug classes recently tried for pain relief. The impact has so far been low and side effects may dramatically limit their use.

Clinical view on pain treatment in cancer

Pain is a subjective experience. Individual treatment is needed, as ‘only the patient feels how much pain hurts, in what way it hurts and what helps’.

The pain signal calls attention to damage or malfunctioning in the tissue. Pain relief is essential to prevent the suffering patient from gradual deterioration and increasing stress signals to the brain. Continuous signalling is non-functional. Unfortunately, the physiology of pain and pain-relieving mechanisms gradually change with time in the afflicted patient. Nociceptors in the periphery are up-regulated and regulatory inhibitory pain tracts from the brain stem to the spine are attenuated so that pain signals are continuously amplified at the spinal level. Several targets for pain relief are physiologically down regulated during long-term pain. Therefore, common analgesics lose their effect over time even though doses are gradually increased. The exact mechanisms for this are not known, e.g. opioid insensitivity. Formation of an allosteric binding site changing the receptor properties or accumulation of metabolites with receptor antagonistic properties has been suggested. Also, opioid receptors taken from the cell surface into the cell resulting in less sensitivity is another possible mechanism. This has led to the concept of ‘morphine rotation’ in which one opioid is switched for another. Switching drug can result in better pain relief despite far lower than equi-analgesic doses being used. In a phase of resurgence, methadone is often used because of its unique receptor-binding properties. Co-administration of opioids acting on different receptors has become of interest. Thus, oxycodone supposed to have some kappa agonistic properties, may offer enhanced analgesia.

Neuropathic/neurogenic pain is common due to pressure of tumours on nerve tracts. This type of pain has always been difficult to treat and available drugs only give partial pain relief to a minority of patients. Current research points to promising results with the N-methyl-D-aspartate non-opioid receptor complex as a target. Amitriptyline has been the drug of choice but debilitating side effects hamper its use. New drugs such as gabapentin and pregabalin originally indicated for epilepsy have been introduced. Although frequently used, the clinical efficacy is limited.

In parallel, non-pharmacological methods, evidenced-based or not, are increasing in popularity. A wide range of methods other than drugs can be used for successful pain management. Specialists can add different types of nerve blockades, use spinal administration of drugs or choose other methods of controlled analgesic delivery. Complementary pain-relieving methods in clinical oncology such as low dose cytotoxic drugs or radiotherapy to minimise tumour pressure and radioactive strontium to destroy bone metastases or bisphosphonates to modify destructive bone catabolism may improve pain relief.

Conclusion

More effort has to be focussed on the concept of pain and pain behaviour taking into account sociological, psychological and emotional aspects as well as past pain experiences and coping strategies to achieve successful pain treatment in cancer.

Pain should be treated individually on the basis of a complete pain analysis:

• A well-informed and confident patient is a prerequisite for successful treatment
• Treatment of pain must be quality assured
• Acetaminophen and morphine are the basis of pharmacological pain treatment
• Anti-inflammatory agents are used only for inflammation in the pain diagnosis
• Combinations of analgesics should be avoided if individualized optimal treatment is needed. A fixed drug combination of codeine and acetaminophen can be accepted for ambulatory patients

Acknowledgement

The author would like to thank Dr Stephen Butler, Pain Clinic, Uppsala University Hospital, Uppsala, Sweden, for the valuable comments on the submitted manuscript.

Author

Professor Per Hartvig-Honoré, PharmD, PhD
Professor in Pharmacokinetics
Department Pharmacology and Pharmacotherapy
Farma, University of Copenhagen
2 Universitetsparken
DK-2100 Copenhagen, Denmark