1. Niazy Burhan Aldin PhD Clinical Pharmacy
Pain
Niazy Burhan Aldin
PhD Clinical Pharmacy

2. Definition Pain can be defined as:
‘An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in
terms of such damage’.

5. Neurotransmitters and pain
Various neurotransmitters in the dorsal horn of the spinal cord are involved in pain modulation. These include amino acids such as glutamate and gamma -aminobutyric acid (GABA), monoamines such as noradrenaline and 5-hydroxytryptamine (5-HT, serotonin) and peptide molecules, of which the opioid peptides are the most important. Opioid receptors are found in both the CNS and the periphery; in the CNS they are found in high concentrations in the limbic system, the brainstem and the spinal cord.

6. Assessment of pain
Evaluation of pain should include a detailed description of the pain and an assessment of its consequences. There should be a full history, psychosocial assessment, medication history and assessment of previous pain problems, paying attention to factors that influence the pain. Diagnostic laboratory tests, imaging, including plain radiography, computer tomography (CT) and magnetic resonance imaging (MRI), and diagnostic nerve blocks may aid confirmation of the diagnosis.

7. Managements
Acute pain usually results from noxious stimulation as a result of tissue damage or injury. It can be managed effectively using analgesic drugs and is often self-limiting. persistent pain may be considered as pain which continues
beyond the usual time required for tissue healing. Treatment may involve specialist pain management services, hospices and a multidisciplinary approach that assesses and manages patients using a bio psychosocial approach.

8. Analgesic ladder
The World Health Organization (WHO) analgesic ladder (Fig. 33.2) forms the basis of many approaches to the use of analgesic drugs. There are essentially three steps: non-opioid analgesics, weak opioids and strong opioids. The analgesic efficacy of non-opioids, such as paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. aspirin, ibuprofen and diclofenac), is limited by side effects and ceiling effects, that is, beyond a certain dose, no further pharmacological
effect is seen. If pain remains uncontrolled, then a weak opioid, such as codeine or dihydrocodeine, may be helpful.

10. Strong opioids, of which morphine is considered the gold standard, have no
ceiling effect and therefore increased dosage continues to give increased analgesia but side effects often limit effectiveness. Adjuvant drugs, such as corticosteroids, antidepressants or anti-epileptics, may be considered at any step of the ladder

11. Analgesic drugs Paracetamol
Despite being used in clinical practice for over 50 years and much investigation, the mechanism by which paracetamol exerts its analgesic effect remains uncertain. Inhibition of prostaglandin synthesis within the CNS has been proposed, although this is probably not the only mechanism. Interaction with the serotonin (Tjolsen et al., 1991) and endocannabinoid (Högestätt et al., 2005) neurotransmitter systems have been
demonstrated in animal models.

13. Non-steroidal anti-inflammatory drugs
Mode of action
NSAIDs exert their analgesic and anti-inflammatory effects through inhibition of the enzyme cyclo-oxygenase. NSAIDs are used widely to relieve pain, with or without inflammation,
in people with acute and persistent musculoskeletal disorders.
In single doses, NSAIDs have superior analgesic activity compared to paracetamol (Hyllested et al., 2002). In regular higher dosages, they have both analgesic and anti-inflammatory effects, which makes them particularly useful for the treatmentof continuous or regular pain associated with inflammation.

14. Guidance on NSAID use
The lowest effective dose of NSAID or COX-2 selective inhibitor
should be prescribed for the shortest time necessary. The need for long-term treatment should be reviewed periodically.
Prescribing should be based on the safety profiles of individual
NSAIDs or COX-2 selective inhibitors, on individual patient
risk profiles, for example, gastro-intestinal and cardiovascular.
Prescribers should not switch between NSAIDs without careful
consideration of the overall safety profile of the products and
the patient's individual risk factors, as well as the patient's preference Concomitant aspirin, and possibly other antiplatelet drugs, greatly increases the gastro-intestinal risks of NSAIDs and severely reduces any gastro-intestinal safety advantages of COX-2 selective inhibitors. ِAspirin should only be co-prescribed if absolutely necessary

16. Weak opioids
Weak opioids are prescribed frequently, either alone or in combination with other analgesics, for a wide variety of painful disorders. There are three major drugs in this group, codeine, dihydrocodeine and dextropropoxyphene, which are recommended as step 2 of the WHO analgesic ladder for pain that has not responded to non-opioid analgesics. Despite this recommendation, there is little data which demonstrates that weak opioids are of any benefit in the relief of persistent pain, and it may be more beneficial to use a smaller dose of a strong opioid.

17. Strong opioids Morphine
Morphine is the ‘gold standard’ strong opioid analgesic. It is available for administration by a range of administration routes, including oral, rectal and injectable formulations and has a duration of action of about 4 h after oral administration. A usual starting dose is 5–10 mg every 4 h, and the patient should be advised to take the same dose as often as is necessary for breakthrough pain. It may be necessary to double the dose every 24 h until pain relief is achieved, although a slower
dose escalation will often suffice

20. Other strong opioids
Opioids such as pethidine and dextromoramide offer little advantage over morphine in that they are generally weaker in action with a relatively short duration of action (2 h). Dipipanone is only available in a preparation which contains
an antiemetic (cyclizine), and increasing doses lead to sedation and the risk of developing a tardive dyskinesia with long-term use. Methadone as a long elimination half-life of 15–25 h, and accumulation occurs in the early stages of use. It has minimal side effects with long-term use and some patients who experience serious adverse effects with morphine may tolerate methadone.

21. hydromorphone or oxycodone better than morphine but there is no evidence to suggest which patients achieve the best effect with either of these drugs.
Fentanyl is available as a transdermal formulation for long-term use. The patch is designed to release the drug continuously
over 3 days. When starting the drug, alternative analgesic therapy should be continued for at least the first 12 h until therapeutic levels are achieved, and an immediate acting opioid should be available for breakthrough pain. Patches are
replaced every 72 h.

22. Tramadol
Tramadol is a centrally acting analgesic that has opioid agonist activity and also has potent monoamine reuptake properties
similar to many antidepressants. Indeed, tramadol appears to have intrinsic antidepressant activity. It is not as potent as morphine and efficacy is limited by side effects, including an unfavourably high risk of drowsiness and nausea and vomiting.
Its monoaminergic activity appears to be valuable in the management of neuropathic pain and hence may be an acceptable alternative to a weak opioid.

23. Adverse effects of opioids
The adverse effects of opioids are nearly all dose related, and tolerance develops to the majority with long-term use.
Respiratory depression
Respiratory depression is potentially dangerous in patients with impaired respiratory function, but tolerance develops
rapidly with regular dosing. It can be reversed by naloxone

24. Sedation Nausea and vomiting
Sedation is usually mild and self-limiting. Smaller doses, given
more frequently, may counteract the problem. Rarely, dexamfetamine or methylphenidate has been used to counteract this effect.
Nausea and vomiting
Antiemetics should be co-prescribed routinely with opioids
for the first 10 days. Choice of antiemetic will depend upon
the cause, and a single drug will be sufficient in two-thirds of
patients. Where nausea is persistent, additional causes should be sought and prescribing reviewed. If another antiemetic is used, it should have a different mode of action Constipation
Opioids reduce intestinal secretions and peristalsis, causing a
dry stool and constipation. Unlike other adverse effects constipation
tends not to improve with long-term use, and when
opioids are used on a long-term basis most patients need a
stool softener (e.g. docusate sodium) and a stimulant laxative
(e.g. senna) regularly

25. Tolerance, dependence and addiction
Persistent treatment with opioids often causes tolerance to the analgesic effect, although the mechanism remains unclear
Smooth muscle spasm
Opioids cause spasm of the sphincter of Oddi in the biliary tract and may cause biliary colic, as well as urinary sphincter spasm and urinary retention. Thus, in biliary or renal colic, it may be preferable to use another drug without these effects.

26. Local anaesthetics
Local anaesthetic drugs, such as lidocaine and bupivacaine, produce reversible blockade of neural transmission in autonomic
sensory and motor nerve fibers by binding to sodium channels in the axon membrane from within, preventing sodium ion entry during depolarization. The threshold potential is not reached, and consequently the action potential is not propagated .Local anaesthetic drugs injected close to a sensory nerve or plexus will block the conduction of nerve impulses, pain from sensory fibres and provide excellent analgesia

27. Non-opioid analgesics
Nefopam is a drug which is chemically related to orphenadrine and diphenhydramine, however, it is neither an opioid, anti-inflammatory drug nor an antihistamine. The mechanism of analgesic action remains unclear. As a nonopioid, it is not associated with the problems of dependence and respiratory depression. The drug has a very high number of dose-related side effects in clinical use that may be linked to its anti-cholinergic actions. Nefopam may be useful in asthmatic patients and in those who are intolerant of NSAIDs.

28. Adjuvant medication
In some types of pain, such as cancer pain or neuropathic pain, the addition of non-analgesic drugs to analgesic therapy
can enhance pain relief. A list of some adjuvant drugs is given in Table It should be remembered that some drugs such
as tricyclic antidepressants (TCAs) have intrinsic analgesic activity, perhaps related to their ability to affect 5-HT and noradrenergic neurotransmission.

30. Clinical use of antidepressants in persistent pain
When used in pain management, it is usual to start with a very low TCA dose, for example, amitriptyline 10–25 mg at night and to titrate upwards according to response and adverse effects. Within clinical trials TCA doses have varied considerably but most are lower than used in psychiatry, in the order of amitriptyline 50–75 mg/day.

31. Anti-epileptics
Include trigeminal neuralgia, glossopharyngeal neuralgia, various neuropathies, lancinating pain arising from conditions such as postherpetic neuralgia and multiple sclerosis and similar pains that may follow amputation or surgery. Several
classes of drugs show anti-epileptic activity and these can be broadly classed as sodium channel blockers (carbamazepine phenytoin), glutamate inhibitors (lamotrigine) voltage gated calcium channel ligands (gabapentin, pregabalin) GABA potentiators (sodium valproate, tiagabine) or drugs showing a mixture of these effects (topiramate).

32. Anxiolytics
Benzodiazepines may be used for short-term pain relief in conditions associated with acute muscle spasm and are sometimes prescribed to reduce the anxiety and muscle tension associated with persistent pain conditions. Many authorities believe that they reduce pain tolerance and there is good evidence that they can reduce the effectiveness of opioid analgesics, although the mechanism by which this occurs is unclear. Clonazepam has been used in the management of neuropathic pain

33. Antihistamines Skeletal muscle relaxants
These agents were introduced into the management of persistent pain because of their sedative muscle relaxant properties. These actions are non-specific and it is not clear
whether the clinical effect is mediated centrally or peripherally
Skeletal muscle relaxants
Drugs described in this section are used for the relief of muscle spasm or spasticity. It is essential that the underlying cause of the spasticity and any aggravating factors such as pressure sores or infections are treated. The Alfaα2-adrenergic agonist tizanidine has potent muscle relaxant activity and is an alternative to baclofen. It may also have some direct analgesic effects.

34. Neuropathic pain
Neuropathic pain may be defined as ‘pain arising as a direct consequence of a disease or lesion affecting the somatosensory system’ and may occur as a result of pathological damage to nerve fibres in a peripheral nerve or in the CNS (see Table 33.3). Neuropathic pain may be spontaneous in nature

37. Phantom limb pain

38. Ref—Roger5th edition chapter 33
All the cases is recommended in the end of chapter