PHARMACOLOGY OF PAIN MANAGEMENT

Question 1

2 TYPES OF PAIN

Answer 1

NOCICEPTIVE AND NEUROPATHIC

Question 2

NOCICEPTIVE PAIN?

Answer 2

(INFLAMMATORY)
DESCRIBES PAIN RESULTING FROM TRAUMATIC INJURY TO TISSUE

• OFTEN TIME LIMITED

Question 3

NEUROPATHIC PAIN?

Answer 3

PAIN RESULTING FROM NEURONAL DAMAGE/CHANGE

• OFTEN CHRONIC, PART OF ‘TOTAL PAIN’
• ASSOCIATED WITH UNPREDICTABLE AND OFTEN DEBILITATING BOUTS OF SHARP SHOOTING OR BURNING PAIN
• OFTEN ASSOCIATED WITH TINGLING OR PARAESTHESIAS (PINS AND NEEDLES SENSATION)
• NUMBNESS AND THROBBING OF REGIONS IS ALSO SEEN IN NEUROPATHIC PAIN, BUT IT LACKS THE LARGE INFLAMMATORY RESPONSES AND LOCALISED EFFECTS ASSOCIATED WITH NOCICEPTIVE PAIN

Question 4

WHAT TYPE OF FIBRE DETECTS TISSUE DAMAGE THAT RESULTS IN A PAINFUL SENSATION?

Answer 4

FREE-NERVE ENDING FIBRES (SITUATED JUST UNDER THE SKIN, RESPOND TO TRAUMATIC INJURY TO THE SKIN AND ALSO TO TEMPERATURE CHANGES)

Question 5

EXAMPLES OF NOCICEPTIVE AND NEUROPATHIC PAIN?

Answer 5

NOCICEPTIVE: ANGINA, ARTHRITIS, ENDOMETRIOSIS, ULCER, LOWER-BACK PAIN..

NEUROPATHIC: CANCER (MALIGNANT PAIN), PHANTOM LIMB, COMPLEX REGIONAL PAIN SYNDROME, POST-HERPETIC SYNDROME (SHINGLES) –> ALL LINKED TO CHANGES IN NEURAL ACTIVITY (E.G. FOR SHINGLES, THE HERPES VIRUS RESIDES IN THE DORSAL ROOT GANGLION OF THE SENSORY SYSTEM)

Question 6

WHAT IS THE NAME OF THE SENSORY TRACTS THAT CARRY PAIN AND TEMPERATURE SIGNALS UP TO THE BRAIN?

Answer 6

THE SPINOTHALAMIC TRACTS (ANTERIOR AND LATERAL)

Question 7

WHICH THEORY DESCRIBES HOW RUBBING A PAINFUL AREA CAN REDUCE THE FEELING OF PAIN?

Answer 7

GATE CONTROL DESCRIBES THE MECHANISM BY WHICH ACTIVATION OF MECHANORECEPTORS (RUBBING) OR ACTIVATION OF DESCENDING TRACTS CAN REDUCE THE TRANSMISSION OF PAIN AT THE LEVEL OF THE SPINAL CORD, BY INCREASING ACTIVATION OF LOCAL INHIBITORY INTERNEURONS OR DIRECTLY INHIBITING THE TRANSMISSION NEURONS OF THE SPINOTHALAMIC TRACTS.

Question 8

ANALGESICS, MEANING?

Answer 8

(‘a’ - no; ‘algesia’ - pain)

Question 9

two main groups of analgesic for nociceptive pain

Answer 9

NSAIDs Non-steroidal anti-inflammatory drugs

Opioids

Question 10

Non-steroidal anti-inflammatory drugs (NSAIDs)

Answer 10

• FOR NOCICEPTIVE PAIN

This group includes some of the most commonly used, over-the-counter, drugs, such as aspirin and ibuprofen. NSAIDs are used widely in the clinic for their four main properties:

Anti-inflammation - this may take days/weeks to reach peak effect
Anti-pyretic - reduces fever by preventing PGE2 effect on the hypothalamus
Analgesic - rapid pain relief via an action on both central and peripheral nervous system
Anti-coagulant - by preventing thromboxane (TxA2) dependent platelet aggregation

They achieve all of these effects by preventing the breakdown of arachidonic acid (derived from membrane phospholipids) by inhibiting cyclo-oxygenase (COX) enzymes. This decreases the production of prostaglandins (PG) and thromboxane (TxA2).

At the neuronal level, under painful conditions prostaglandins are produced which bind to prostanoid receptors. This triggers a second messenger cascade that increases the likelihood of the neuron depolarising and firing.

By preventing prostaglandin production the NSAID reduces neuronal firing, decreasing the pain sensation.

Question 11

4 MAIN PROPERTIES OF NSAIDs

Answer 11

Anti-inflammation - this may take days/weeks to reach peak effect
Anti-pyretic - reduces fever by preventing PGE2 effect on the hypothalamus
Analgesic - rapid pain relief via an action on both central and peripheral nervous system
Anti-coagulant - by preventing thromboxane (TxA2) dependent platelet aggregation

Question 12

CLINICAL USE OF OPIOIDS?

Answer 12

Clinically, opioids are used for:

Analgesia - chronic and acute pain relief.
Anaesthesia - as an anaesthetic adjunct, providing additional anaesthesia and pain relief.
Antitussive effects - they dampen down the cough reflex (an old cough mixture used to be kaolin and morphine!).
Antidiarrhoeal effects - they slow down peristalsis in the gut, increasing the opportunity for water resorption, firming up stools.

They are most commonly used in coronary care (pre and post surgery) and in cancer care situations, where pain relief is key.

Opioids are the top of the pain ladder and the best analgesic we currently have available is morphine.

Question 13

BEST ANALGESIC CURRENTLY AVAILABLE?

Answer 13

MORPHINE

Question 14

NUMBER AND NAMES OF OPIOID RECEPTORS?

Answer 14

• THERE ARE 4 OPIOID RECEPTORS
• MU, MOP
• KAPPA, KOP
• DELTA, DOP
• ORPHAN RECEPTOR, NOP

Question 15

HOW DO OPIOIDS WORK?

Answer 15

Opioids reduce neuronal activity in the central and peripheral nervous system by binding to the opioid receptors and causing:

Decreased opening of voltage-dependent Ca2+ channels

Increased K+ outflow via KATP and KIR channels

Decreased Ca2+ release from intracellular stores

Decreased exocytosis of transmitter vesicles

This hyperpolarises neurons reducing the likelihood of firing, decreasing the transmission of the pain signal. They also increase activity in the descending inhibitory pathways to reduce transmission of the pain signal at the level of the spinal cord

Question 16

TRAMADOL?

Answer 16

Tramadol is a synthetic opioid that also combines elements of anti-depressant drugs (it also acts as a Serotonin Noradrenaline Reuptake Inhibitor (SNRI)). It is a very effective pain killer and is generally well tolerated, but can associated with some disturbing side effects such as hallucinations and can induce dependency, so is used very carefully.

Question 17

DIFFERENCES BETWEEN NSAIDs AND PARACETAMOL?

Answer 17

The differences between NSAIDs and paracetamol are that NSAIDs have a strong peripheral and anti-inflammatory effect, whereas paracetamol works principally within the central nervous system and has no short-term reduction of inflammation.

Question 18

PARACETAMOL?

Answer 18

Paracetamol is an interesting drug, very similar to NSAIDs. It is a very good analgesic and a very good antipyretic, but has little anti-inflammatory effect. It works via the same mechanism as the NSAIDs, blocking the breakdown of arachidonic acid to prostaglandins via inhibition of the COX enzymes. It has a preferential effect on COX-2. It can also activate cannabinoid receptors and vanilloid receptors.

Question 19

TRPV1 (transient receptor potential cation channel V1)

Answer 19

TRPV1 (transient receptor potential cation channel V1) is a vanilloid receptor that is found on nociceptors and is involved in detection of heat and pain. This receptor is also where capsaicin binds, making the link between heat and pain that you get when eating chillies.

Question 20

TREATING NEUROPATHIC PAIN COMPARED TO NOCICEPTIVE PAIN MANAGEMENT?

Answer 20

Neuropathic pain is more difficult to treat than nociceptive pain, as it comprises both physical and psychological components.

Some people do have a positive response to opioids, it can be a good treatment for phantom limb pain, however, most forms of neuropathic pain are generally insensitive to both NSAIDs and opioids.

Question 21

Two groups of drugs are currently commonly used to treat neuropathic pain:

Answer 21

Tri-cyclic antidepressants, e.g. amitriptyline, nortriptyline
Antiepileptics e.g. Gabapentin, carbamazepine

These both act to increase the inhibition of the pain pathways, but in different ways.

Question 22

Tri-cyclic antidepressants

Answer 22

Tri-cyclic antidepressant (TCA) drugs have 5 main actions, but their main mechanism of action is to block the reuptake of both 5HT (serotonin) and noradrenaline. By increasing the levels of 5HT and NA, they increase the activity in the descending pathways which can block pain transmission. They also act in a positive way to improve arousal and mood which can aid pain management.

They also block adrenoreceptors, histamine receptors and muscarinic receptors. Their activity as an antihistamine can block inflammatory responses and blocking adrenoreceptors and muscarinic cholinergic receptors can alter smooth and striated muscle function, learning to relaxation, vasodilatation and sedation, which all help with pain management.

Question 23

Antiepileptics

Answer 23

Antiepileptics such as gabapentin and carbamazepine act to reduce the hyperactivity in neurons that is associated with neuropathic pain. By dampening down activity they reduce pain sensation. Gabapentin’s mechanisms of action is unclear but it can block voltage dependent calcium channels, which would decrease hyperactivity. Carbamazepine (a drug that is very good at treatment of trigeminal neuralgia - facial neuropathic pain), also acts in an unknown way, but it has been shown to block voltage dependent sodium channel, which would also decrease neuronal activity.

Question 24

MOST COMMON COMBINATION THERAPY FOR NEUROPATHIC PAIN?

Answer 24

It is possible to prescribe a combination of antidepressant and antiepileptic, amitriptyline and gabapentin is a common combination.

Question 25

WHICH ANTIEPILEPTIC DRUG USED IN MANAGEMENT OF NEUROPATHIC PAIN DOESN’T WORK WEEL WITH OTHER DRUGS AND SHOULD ALWAYS BE PRESCRIBED ALONE?

Answer 25

carbemazepine

Question 26

RUBEFACIENTS?

Answer 26

Literally named for the effect that they cause (‘rube’ - red; ‘fascia’ - connective tissue found under skin), rubefacients are counter-irritants. these drugs are used for mild to moderate localised musculoskeletal pain.

Question 27

RUBEFACIENTS - MECHANISM OF ACTION?

Answer 27

Rubefacients are applied to the skin to stimulate vasodilatation, which leads to reduction of localised inflammatory responses caused by the painful stimulus/tissue damage and therefor reduces pain transmission at the very peripheral level only.

Rubefacients do not penetrate deeply into the skin so provide only a very localised region of relief. They often contain irritant substances such as nicotine, menthol, camphor or capsicum (chilli/red pepper). The extract of capsicum, capsaicin, is thought to be useful in managing local neuropathic pain. A common inclusion in rubefacients are salicylate compounds, plant compounds that include salicylic acid, or aspirin; these are one sub-group of the non-steroidal anti-inflammatory drugs.

Question 28

Why might rubbing a rubefacient into the skin improve its effectiveness?

Answer 28

• RUBBING OF A DRUG INTO THE SKIN INCREASES THE PENETRATION, ALLOWING IT TO HAVE A DEEPER EFFECT ON THE LOCAL CIRCULATION
• THE ACT OF RUBBING ALSO ACTIVATES MECHANORECEPTORS WHICH MAY ALSO ‘CLOSE THE GATE’ ON PAIN TRANSMISSION

Question 29

ANAESTHETICS?

Answer 29

Anaesthetics (‘a’ - no; ‘aesthesia’ - sensation), block pain transmission from reaching consciousness. They can act either at the local level, as local anaesthetics, or across the whole body, as general anaesthetics.

Local anaesthetics are only ‘local’ as they are administered in low doses to affect small localised regions around the site of administration, administer enough and they will as a general!

Question 30

Epidural anaesthesia

Answer 30

Epidural is a form of LOCAL anaesthesia commonly used to relieve pain during childbirth. It reduces pain but still allows the mother to respond to changes in pressure and be able to push. So why doesn’t the anaesthetic numb everything, including motor neurons?

The reason why epidural seems to have more effect on sensory rather than motor is that, for some reason, sensory neurons are significantly more sensitive to the effects of local anaesthetics than the motor neurons. Interestingly, there are differential sensory effects of various anaesthetics too. Cold sensation is generally not as affected by epidural as other sensations, and, as noted above, with epidural analgesics, pain is removed but not pressure sensation.

This is probably linked to the levels of myelination of the neurons, and ease of entry of the anaesthetic. Nonetheless, epidurals can have an effect on the motor system, but this is drug and concentration dependent, for example while lidocaine provides great anaesthesia, midazolam (a benzodiazepine, which increases GABA transmission) is a muscle relaxant and a very good sedative.

• INJECTION INTO THE EPIDURAL SPACE BETWEEN THE VERTEBRAL COLUMN AND THE SPINAL CORD

Question 31

WHICH NEURONS ARE MORE SENSITIVE TO THE EFFECTS OF LOCAL ANAESTHESIA, SENSORY OR MOTOR?

Answer 31

sensory neurons are significantly more sensitive to the effects of local anaesthetics than the motor neurons

Question 32

How do local anaesthetics work?

Answer 32

The mechanism of action is similar for most local anaesthetics, they act by blocking the voltage-gated sodium channels (NaV in the figure) of neurons to prevent action potential firing.

Most local anaesthetics enter the cell through the membrane in an unionised from, and become ionised in the intracellular space. In this form it can block the inside of the Na+ channel.

Question 33

MECHANISM OF ACTION FOR DRUGS USED TO GENERATE GENERAL ANAESTHESIA VIA INHALATION?

Answer 33

Many of the drugs used to generate general anaesthesia via inhalation (for example: propofol and thiopental) have various mechanisms of action. The overarching view is that they suppress consciousness through a reduction of activity within the CNS, with agents acting on both inhibitory (GABA) and excitatory (glutamate) pathways.

Question 34

WHY DO LOCAL ANAESTHETICS MIGHT NOT WORK AS WELL IF THE TISSUE IS INFLAMMED?

Answer 34

• BECAUSE THEIR ABILITY TO WORK IS pH-DEPENDANT AND THE INFLAMMATORY SOUP IN DAMAGED TISSUE IS GENERALLY ACIDIC
• LOCAL ANAESTHETICS IONISE IN ACIDIC pH WHICH REDUCES THEIR ABILITY TO CROSS THE NEURONAL MEMBRANE TO ATTACH TO THE Na+ CHANNEL

Question 35

Side effects of analgesics - NSAIDs

Answer 35

Generally the NSAIDs are well tolerated at low doses and with short term usage. However, with longer term use and with stronger NSAIDs (such as naproxen) there are a number of common side effects seen.

The most common side effect with the NSAIDs is gastrointestinal (GI) upset, including heartburn, nausea, vomitting, diarrhoea and bleeding/ulceration. this is because of the block of COX1 enzymes which are responsible for homeostasis of the gut mucosa, which leads to damage of the lining of the stomach and intestines.

Due to the interaction between NSAIDs and thromboxane production, any tissue damage (including gastric mucosal damage or any surgery needed etc) may lead to increased bleeding. The blood thinning effect take a few days to disappear after the NSAID are terminated which is why patients are always asked to stop taking any NSAID three days before surgery at least.

Question 36

NSAIDs FOR PATIENTS WITH GI PROBLEMS?

Answer 36

There are specific COX-2 inhibitors, such as Celecoxib and Etoricoxib, which have been designed to have strong anti-inflammatory effects without having some of the side effects associated with non-specific COX inhibitors. These drugs are useful in patients with gastrointestinal problems, but have been associated with cardiovascular side effects (e.g. the high profile problems with Vioxx (rofecoxib) which led to it’s withdrawal).

Question 37

What is prescribed alongside stronger and/or long-term NSAIDs?

Answer 37

In order to counteract the GI effects of NSAIDs, proton-pump inhibitors (PPI e.g. ompeprazole) are always given when patients are prescribed stronger and/or long-term NSAIDs. These stop the H+K+-ATPase pumps producing stomach acid and reduce the damage.

Question 38

ONE OF THE MOST COMMON INDICATORS OF NSAIDs INTOXICATION?

Answer 38

One of the most common indicators of NSAID intoxiation is interestingly, tinnitus. It’s an early sign of overdose often associated with long term use of the salicylate subgroup of NSAIDs (which includes aspirin). For an unknown reason, the auditory nerves are susceptible to NSAID use and this results in spontaneous activity leading to a perception of ringing or buzzing.

Question 39

HOW CAN OPIOID INTOXICATION BE REVERSED?

Answer 39

Opioid intoxication can be reversed by using an opioid antagonist, such as naloxone and naltrexone. Naltrexone is also used long-term to reduce the effect of subsequent use in the management of both opioid and alcohol dependency.

Question 40

OPIOIDS SIDE EFFECTS?

Answer 40

One of the biggest problems with the opioids is the potential for development of dependency. Painkiller addiction is a huge problem worldwide, but is very heard to tease out from overall drug addiction numbers.

Common side effects of the opioid drugs are the result of the dampening down of neuronal activity:

Constipation - as peristalsis and gut activity is slowed
Nausea and vomitting - due to opioid action at the brainstem vomitting centre
Conscious depression and mood alterations - due to dampening of cortical activity
Respiratory depression - due to depression of activity in brainstem respiratory centres
Miosis (pinpoint pupils) - as a result of dampening of the sympathetic drive

Question 41

% OF POPULATION EXPERIENCING MIGRAINE?

Answer 41

10%

Question 42

Primary headache types:

Answer 42

Tension
Sinus
Migraine
Cluster
Medication overuse

Question 43

TENSION HEADACHES

Answer 43

These are undoubtedly the most common form of headache and are associated with physical and mental tension. Any changes to the vasculature, e.g. by dehydration or stress may lead to vasospasm or increases in pressure that are felt as a headache. Tension headaches are normally bilateral, affecting both sides of the head and often felt at the back of head as well. They respond well to NSAIDs and the triggers can often be identified using a headache diary.

Question 44

SINUS HEADACHES

Answer 44

These are the result of pressure in the sinuses as a result of inflammation of blocking leading to an increased pressure being felt over the location of the sinuses. The frontal sinuses are located above the bridge of the nose and eyes, the maxillary sinuses to the side of the nose underneath the eyes, giving rise to a characteristic pattern of pain. This type of headache is often remedied using decongestants or antihistamines to reduce inflammation and blockage.

Question 45

MIGRAINE

Answer 45

One of the most painful and debilitating forms of headache, migraine has a number of stages and may last for days before resolving. Migraine onset if often preceded by warning signs or auras, which form the prodromal and aura stages of migraine, before the full migraine headache begins, so severity increases over time. Migraine headache is normally unilateral, affecting most the head on one side, with a focal point generally located behind the eye. It is often associated with some characteristic sensitivities, including light (photophobia) and sound (phonophobia). NSAIDs and anti-emetics (anti-vomiting drugs) are often the first approaches to managing migraine, opioids are generally avoided and often ineffective.

Migraine is often associated with gastrointestinal upset, nausea and vomiting; these are the most common signs and symptoms in children, who tend to experience gastric migraines, but this tells us something about the pathology.

Question 46

CLUSTER HEADACHES

Answer 46

Cluster headaches are headaches with a rapid onset and strong severity that are associated with changes in the autonomic nervous system. They are unilateral and focussed around the eye and have no warning symptoms, but are associated with increased excretions, running eyes and nose as a result of involvement of the trigeminal nerve (CNV). they are called cluster as you may have a number of these headaches occurring in close succession and then a period of time with no headaches. Attacks can be managed using triptans as for migraine, with blood pressure medication used prophylactically as for migraine.

Question 47

MEDICATION OVERUSE HEADACHE?

Answer 47

Ironically taking too many painkillers may lead to the onset of medication overuse headaches. Weaning off of the medication and behaviour change is key to relieving the headaches. Education and support are vital for the patient as well as developing preventative measures to reduce the need for painkillers.

Question 48

MOST COMMON FORM OF HEADACHE?

Answer 48

TENSION HEADACHES

Question 49

MOST COMMON TREATMENT FOR MIGRAINE?

Answer 49

migraine is to use triptans (e.g. sumatriptan)!

These drugs are 5-HT1 agonists and stop the vasospasm that is linked to headache and dampen down overactivity in the pain pathway, through increasing activity in the descending pathways. However, triptans are not useful for many people with other underlying conditions, especially cardiovascular and pulmonary disorders. Blood pressure medications are often use prophylactically to reduce migraine incidence.

Question 50

NERVE BLOCKS?

Answer 50

Many invasive procedures that are utilised in pain management are dependent on the use of anti-inflammatory agents or anaesthetics to alleviate the pain. The most commonly used of these are nerve blocks, where needles are inserted into joints or trigger points to inject substances such as anaesthetics to block nerve conduction or reduce inflammation (usually steroids).

Agents can also be administered using indwelling catheters or via implanted pumps.

Question 51

WHY ARE NSAIDs AVOIDED BEFORE SURGICAL INTERVENTIONS?

Answer 51

BECAUSE THEY MAY LEAD TO INCREASED BLEEDING

Question 52

AT WHAT PAIN LEVEL DO RUBEFACIENTS WORK?

Answer 52

PERIPHERAL NOCICEPTORS

Question 53

WHICH TYPE OF HEADACHE IS UNILATERAL WITH AUTONOMIC INVOLVEMENT?

Answer 53

CLUSTER

• ACTIVATION OF THE TRIGEMINAL NERVE IN THE FACE LEADS TO RUNNY NOSE AND EYES AND PINPOINT PUPILS

Question 54

WHAT WOULD A PUPIL LOOK LIKE IN OPIOD OVERDOSE AND WHY?

Answer 54

• THE PUPILS BECOME VERY SMALL (PINPOINT, MIOSIS) AS THE SYMPATHETIC NERVOUS SYSTEM, WHICH DILATES THE PUPIL, IS DECREASED

Question 55

WHICH RECEPTOR DO NSAIDs PREVENT ACTIVATION OF?

Answer 55

PROSTANOID (they prevent production of prostaglandins which bind to prostanoid receptors)