Dealing with Pain and Fever in the Pharmacy Why this lecture? Pain: the most common reason for seeking medical advice. Fever: the most common symptom for which parents seek OTC drugs Internal Analgesics: the most commonly sold OTC drugs in the USA and UK.

Pain: “ unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage ” International Association for the Study of Pain Ref: APhA book

Mechanism of Perception of Pain: The sensory component of pain results from transmission of peripheral pain impulses to the CNS by nociceptors and nociceptive nerve fibers. Nociceptors: peripheral pain receptors that are activated by noxious stimuli in the periphery and send pain stimulus to the spinal cord via the nociceptive fibres.

Mechanism of Perception of Pain: Through the dorsal route ganglion dorsal horn of spinal cord Afferent pain impulses Many substances involved: NE, 5-HT, GABA, glycine, endorphin and enkephalin Synapse with Ascending fibres to the brain Efferent fibres to the periphery- complete the circle Many substances are involved in the transmission and modulation of pain Within the dorsal horn of the Sp.C: e.g. Substance P, bradykinin, histamine, prostaglandins Research now: NMDA receptors in the post-synaptic membrane- NMDA antagonists role in neuropathic pain (glutamate activates these receptors chronic pain conditions). Neurons in the thalamus and brain stem release inhibitory transmitters: NE, 5-HT, GABA, glycine, endorphin and enkephalin All these act to block input from excitatory neurotransmitters OTC analgesics have minimal effect within the dorsal horn.

Mechanism of Perception of Pain: normally a balance exists between excitatory and inhibitory neurotransmissions Perceived pain, either acute or chronic occurs when this balance changes, resulting in exaggerated responses and sensitization

Ongoing tissue damage/diseases Pain due to Noxious stimuli (e.g.mechanical, thermal) Ongoing tissue damage/diseases Release of pain-facilitating mediators: prostaglandins, histamine, bradykinen “fight-or-flight” epinephrine release Acute (immediate) Chronic

Categories of Pain:   Analgesics prevent progression. OTC useful in all 3 categories Categories of Pain: Acute: immediate reaction to noxious stimuli.   Analgesics prevent progression. Chronic malignant: ~ associated with any advanced, progressive disorder, not just cancer: MS, AIDS, end-stage renal/hepatic failure, end-stage respiratory disease. Chronic non-malignant: most complex, most misunderstood and least well managed. Related to a progressive debilitating process. e.g low back pain, arthritis, neuropathic pain, headache OTC drugs maybe useful in treatment of all 3 types of pain, either as monotherapy or as adjuncts to non-pharmacologic or prescription therapy Acute and chronic malignant: indications for aggressive drug therapy. Take analgesics on a regular basis to prevent the recurrence of pain not “as needed” > “i-e after the pain recurs” Sometimes additional mechanisms are involved- inflammation > NSAID Chronic non-malignant pain: Analgesics: NOT the primary treatment, only adjuncts. The underlying disorder should be treated, not just the presenting symptom Multi-modal approach: a doctor with pain expertise (anaesthiologist, neurologist), rehabilitation specialist (physiotherapist), mental health professional (psychologist) and a pharmacist.

Types of Pain Somatic Visceral Neuropathic Types of Pain There are three types of pain, based on where in the body the pain is felt: somatic, visceral, and neuropathic. Pain of all three types can be either acute or chronic. Somatic, visceral, and neuropathic pain can all be felt at the same time or singly and at different times. Most cancer patients experience both somatic and visceral pain. Only about 15-20% of all cancer patients report neuropathic pain. The different types of pain respond differently to the various pain management therapies. Somatic and visceral pain are both easier to manage than neuropathic pain. Somatic Pain Somatic pain is caused by the activation of pain receptors in either the cutaneous (body surface) or deep tissues (musculoskeletal tissues). When it occurs in the musculoskeletal tissues, it is called deep somatic pain. Common causes of somatic cancer pain include metastasis in the bone (an example of deep somatic pain) and postsurgical pain from a surgical incision (an example of surface pain). Deep somatic pain is usually described as dull or aching but localized. Surface somatic pain is usually sharper and may have a burning or pricking quality. Visceral Pain "Viscera" refers to the internal areas of the body that are enclosed within a cavity. Visceral pain is caused by activation of pain receptors resulting from infiltration, compression, extension, or stretching of the thoracic (chest), abdominal, or pelvic viscera. Common causes of visceral pain include pancreatic cancer and metastases in the abdomen. Visceral pain is not well localized and is usually described as pressure-like, deep squeezing. Neuropathic Pain Neuropathic pain is caused by injury to the nervous system either as a result of a tumor compressing nerves or the spinal cord, or cancer actually infiltrating the nerves or spinal cord. It also results from chemical damage to the nervous system that may be caused by cancer treatment (chemotherapy, radiation, surgery). This type of pain is severe and usually described as burning or tingling. Tumors that lie close to neural structures are believed to cause the most severe pain that cancer patients feel. Somatic pain most commonly from: muscles, fascia, bones Somatic pain is mostly Myofascial: arises from localised tender area in the muscle or surrounding tissue (trigger points), when pressed reproducible, referred pain pattern Trigger points can occur following injury or immobility of the affected tissues

Pain-associated conditions responsive to OTC analgesics: Headache Myalgia Periarticular pain Arthralgia

Headache (HA) Many HA patients use self-treatment rather than seek medical attention HA amenable to self-treatment: tension type, diagnosed migraine & sinus HA

Headache: A symptom: primary or secondary Results from dysfunction, injury or displacement of pain-sensitive cranial structures. Headache Muscle contraction.Tension HA Vascular HA / Migraine Traction HA caused by inflammation (e.g. meningitis), tumors or hematomas (hemmorrage). They are called traction HA because the underlying pathology causes irritation and stretching of the meninges. These membranes are richly endowed with pain receptors which when stimulated will cause HA. The barin itself has no sensory receptors within its fabric. A lesion within the substance of the brain will therefore not produce pain until it impinges upon adjacent structures. Vascular/ Muscle Contraction HA Other Types of HA e.g. Side effect, sinus HA, eye strain, dental pain Traction HA Chronic daily HA (medication overuse)

Your homework! The International Headache Society (IHS) classification

Headache: Muscle Contraction / Tension HA: Results from tight muscles at upper back, neck, occiput or scalp. Bilateral, diffuse- at top of head- extend. Aching ‘tight’ pressing- gradual in onset, worsens through the day. Associated with emotional stress/anxiety- may last several days (Acute or chronic)   OTC analgesics for acute types Chronic types: physical therapy + relaxation Temporalis, frontalis and occipitalis The most common of all HA 40-90% of people in Western countries Acute: if less than 15 days per month and has no persistent symptoms Chronic: HA occurs more than 15 days per months and last for more than 6 months. Patient generally presents with a history of previous HA over the last few days or weeks.

NEW! Neurological research has isolated the temporalis muscle as the primary center of tension headache pain and possibly common migraine pain (Boyd, 2005) Recently, neurological research has isolated the temporalis muscle as the primary center of tension headache pain and possibly common migraine pain. Although the temporalis muscle is located on the skull, it is technically a jaw muscle and not a scalp muscle, since its sole function is to close the jaw. Medical schools, therefore, leave the study of the temporalis muscle to the dental schools. Dental schools leave the study of headache to the medical schools, so the temporalis muscle and even more importantly, the nerve that services the temporalis, the Trigeminal,  has been largely overlooked as a causative and/or perpetuating source of headache and migraine.

2. Migraine HA (vascular HA) Mainly women (3 times more) Attack: 3 hrs--- up to 3 days (av. 24 hrs) Migraine: recurrent, hemicranial, throbbing Triggers: stress, fatigue, oversleeping, fasting, vasoactive substances in food, caffeine, alcohol. Menses and changes in BP; Maybe caused by medications: nitrates, OCPs, indomethacin, HRTs) IHS: recognises 7 types of migraine BUT for practicality classical OR common Although recently: not purely vascular. Vascular with neurochemical changes that are rooted in a genetic abnormality. 55% of families have mutations on chromosome 19. Vascular component: Vascular HA: distension/ dilatation of intracranial arteries or traction/displacement of intracranial veins or meningial covering. First attack in adolescence or as a young adult. Rarely after age of 50  refer for evaluation to eliminate secondary causes.

Classic Migraine (with aura) Accounts for < 25% of migraine cases visual or neurological aura  over 5-20 minutes and can last for up to 1 hour Within 60 min of aura ending HA starts Pain unilateral, throbbing, moderate to severe, sometimes generalized and diffuse. Physical activity and movement intensify pain. Nausea (1/3 sickness). Photophobia, Phonophobia, fatigue, concentrating difficulty. Migraine 3 phases: Premonitory (prodrome phase): occur hours or possibly days before the headache. Change in the mood or behaviour. Feelings of wellbeing, yawning, poor concentration and food craving. Those features are highly individual but are relatively consistent to each patient. HA with or without aura HA subsides, the patient may feel lethargic, tired and drained before recovery which may take several hors and is termed the ‘resolution phase’. Visual aura: scotomas (blind spots) or fortification spectra (zig-zag lines) or flashing and flickering lights. Neurological: pins and needles typically starts in the hand, migrating up the arm before jumping into face and lips.

Common Migraine (without aura) 75% of sufferers No aura All other symptoms the same

3. Cluster headache Predominantly affects men aged 40-60 HA occurs same time each day, last 10 min-3h 50% of patients: night-time Woken 2-3 h after sleep with steady intense unilateral orbital pain. Conjunctivitis and nasal congestion (watery) is experienced at same side of head as HA Ch.ch: periods of acute attack, typically a number of weeks- few months (1-3 attacks per week) Nausea is usually absent and family history uncommon Referral to the doctor. OTC unlikely to be effective

4. Vascular- Muscle contraction HA: Patients with daily tension headaches and occasional migraines Either type can precipitate the other 5. Other Causes of HA **Sinus Headache: infection/blockage of the paranasal sinuses > inflammation/distension of the sensitive sinus walls. Localised: peri-orbital, forehead area with stooping, blowing nose. Upon awakening, subside after a while OTC analgesics + decongestants Persistent > bacterial infection> Dr.

Headache: All secondary causes of HA except sinusitis need to be referred. Fever, hangover, some NSAIDS (like what?) eye strain, infection (e.g. meningitis), depression, anxiety, glucoma > OTC not effective Temporal arteritis, raised ICP ‘weekend’HA Glucoma: frontal HA with pain in the eye. Sometimes, but not often, the eye appears red and is painful. Vision is blurred and the cornea can look cloudy. In addition, the patient may notice halos around the vision. Meningitis: severe generalized HA associated with fever, an obviously ill patient, neck stiffness, a positive kernig’s sign (pain behind both knees when extended) and latterly a pupuric rash all classically associated with meningitis Meningitis is notoriously difficult to diagnose. Any child has a difficulty in placing the chin on the chest, has a headache and is running a temperature over 38.9 Referred urgently Subarachnoid haemorhage: very intense and severe pain, located in the occipital region. Nausea and vomiting are present and a decreased lack of conciousness is oprominent. Extremely unilikely that a paitent would present in the pharmacy with such symptoms but if so refer immediately. Temporal arteritis

Self-care of HA

Nonpharmacological treatment of HA

C/I to aspirin

Aspirin intolerance

Before surgery…

Myalgia OTC analgesics should be started soon after the injury. Adjunctive: heat, massage. Remobilisation after injury healed is important, otherwise: weak, tight, overly contracted muscles, trigger points may arise R.I.C.E: beneficial. ice, vapo-coolant spray, trigger point injections (= Local anaesthetic to facilitate mobilisation)

Periarticular Pain: injury or inflammation to the tissues surrounding the joint ( joint capsule, ligaments, tendons, bursae) Localised tenderness, pain associated with movement of structure. knee, shoulder, elbow Responds well to OTC analgesics and limitation of movement

Arthralgia: Joint pain often caused by synovitis (inflammation of synovial membrane). Cartilage loss may occur (e.g. in DJD, RA). Osteoarthritis (DJD) In wt bearing joints: hips, knee, lumbar spine Paracetamol is analgesic of choice, wt loss For acute flares: NSAIDs, local heat Reumatoid Arthritis (RA) mainly: multiple joints, fingers, hands, wrist and feet joints warm, red, swollen, motion limited > deformity more than OTC (NSAIDs): education, physical therapy, Eat plenty of sulphur containing foods, such as garlic and onion, and eggs. Sulphur is needed for the repair and rebuilding of bone, cartilage and connective tissue, and aids in the absorption of calcium. Eat plenty of green leafy vegetables, and vegetables of every colour, non-acidic fresh fruit. Eat whole grains (except wheat) such as spelt, kamut, millet and brown rice. Eat oily fish, such as mackerel, herring, sardine, pilchard (avoid the tomato sauce in the tins of fish). Eat fresh (not dried or tinned) pineapple when available as the enzyme Bromelain found in pineapple will help reduce inflammation. Take a tablespoon of linseeds with a couple of glasses of room temperature water every day. Apple cider vinegar is very good for people with arthritis. Reduce saturated fat from animals in your diet and avoid fried foods. Avoid all milk and other dairy produce. You may be alright with goats or sheeps yoghurt. Avoid red meat. Avoid the nightshade family of vegetables (peppers, aubergine or eggplant, tomatoes and white potatoes – also tobacco). The solanine found in these foods can cause pain in the muscles to susceptible people. Avoid table salt (sodium chloride) but include the natural sodium found in foods such as celery – this is needed to keep calcium in solution and not sit on top of your joints. Get your iron from food, but ensure your multimineral supplements does not contain extra iron (unless your Doctor tells you you’re anaemic) – there is some evidence iron may be involved in pain, swelling and joint destruction. You do need some iron though, so eat broccoli, blackstrap molasses, beetroot, peas and, if you are Blood Type O, a little lean organic red meat if this appears to suit you.

Assessment of Pain: Pharmacist should enquire about: Aetiology Duration Location Severity Factors that or pain When to use OTC analgesics?

Acute Pain “The Patient’s Pain Is What They Say It Is”

Measuring Acute Pain Adults Verbal Rating Scales None Mild Moderate Severe Numerical Rating Scales 0 = no pain 10 = worst pain ever Visual Analogue Scales Visual Analogue Scale (VAS): marking on a 10cm line distance that represents pain, measure then record 1-100 47

Measuring Acute Pain Children 3-7 yrs

Fever Fever is defined as a body temperature that is higher than the normal core temperature of 37.8ºC (average 36.4 ºC –37.2 ºC ) Rectal > 38.0 ºC Oral >37.6 ºC Axillary > 37.4 ºC Tympanic > 37.8 ºC Hyperpyrexia: > 41.1 ºC – mental & physical consequences Core temperature is the temperature of the blood that surrounds hypothalamus

Mechanisms of body thermoregulation: temperature-sensitive neurons (in skin and hypothalamus) >>> thermoregulatory centre of the body in the anterior hypothalamus: Behavioural and physiological mechanisms (examples?) to maintain temperature physiological mechanisms are mediated by TSH & catecholamines

Summary: Axillary temperature is 1 degree lower than oral temperature and 2 degrees lower than rectal temperature. Rectal: < 5 yrs/o Oral: > 5 yrs/o Axillary: > 3 mths/o Tympanic > 6 mths/o

Mechanisms of body thermoregulation & Fever: Circadian variation: peak 5-7PM and lowest point 3-5AM Pyrogens: fever-producing substances, that activate the body’s host defence mechanisms. Pyrogens are either exogenous or endogenous Prostaglandins E are released in response to circulating pyrogens ASA and paracetamol inhibit synthesis of PG-E in CNS >> antipyretic activity endogenous pyrogen Fever producing substance released by leucocytes (and Kuppfer cells in particular) that acts on the hypothalamic thermoregulatory centre. Now known to be interleukin-1.

Aetiology of Fever: Microbe-induced fever: bacterial >>> viral Elderly <<< younger people Pathology-induced fever: Non-infectious pathologic causes of fever malignancies, tissue damage (MI, surgery), dehydration, metabolic disorder (hyperthyroidism, gout), antigen-antibody reaction, heat-stroke, CNS inflammation heatstroke A severe and often fatal illness produced by exposure to excessively high temperatures, especially when accompanied by marked exertion. It can manifest by elevated body temperature, lack of sweating, hot dry skin, and neurologic symptoms; unconsciousness, paralysis, headache, vertigo, confusion. In severe cases very high fever, vascular collapse, and coma develop. Synonym: heat apoplexy, heat hyperpyrexia, malignant hyperpyrexia, thermic fever

Aetiology of Fever: Drug-induced fever: Examples: Aspirin, sulfamethoxazole, cephalothin, phenothiazines, TCA, antineoplastics, amphetamines, epinephrine Drug-induced fever: A- Interfering with peripheral heat dissipation (eg, sweating by high doses of anticholinergics) B- basal metabolic rate (eg, thyroid hormones) C- ideosyncrasy D- hypersensitivity reaction (mostly after 7-10 days) E- Method of drug administration: e.g. IV cath., multiple IM inj., excessive rapid infusion of vancomycin F- as a result of the drug-pharmacologic effect: e.g. syphilis bacteria endotoxins, cancerous cells The bacteria causing syphilis is: Triponema Pallidum Jarisch-Herxheimer reaction

Complications of Fever: Serious complications are rare Harmful effects: dehydration, delirium, seizures, irreversible neurologic/muscular damage and coma However, even lower temp can be life-threatening: infants, people with heart D, brain tumor or haemorrhage, CNS infections, preexisting neurologic disorder >> febrile seizures If > 41.1ºC

Febrile Seizures: seizures associated with fever in the absence of another cause (e.g. acute metabolic syndrome, CNS inflammation) in 2-4% of children (6mths-5 years) Complex > 15 mins repetitive during the episode exhibit focal features/signs in children of preexisiting/latent epilepsy Simple No longer than 15 mins do not recur during single episode no focal features No neurologic sequelae

Febrile Seizures: although magnitude and rate of temp are determinants of febrile seizures, however, the temp at which the child will seize is unpredictable. high risk: previous seizure, family Hx, documented CNS disorder. Prophylaxis: antiepileptics (DOC: valproate, diazepam) are reserved for those at high risk. Prevalence of epilepsy may be higher after a febrile seizure.

Measurement of body temperature

Measurement of body temperature Axillary, tympanic, oral, rectal During the course of illness > use same thermometer wash hands thoroughly before and after Types of thermometers: Mercury-in-glass Electronic thermometer Tympanic thermometer Skin thermometer

Types of thermometers: 1. mercury-in-glass might break > injury Its use should be discouraged due to environmental concerns 2. Electronic + register quickly (10-60 sec) digital display- easy to read do not break use of disposable covers eliminates the need for disinfection low risk of injury no mercury toxicity - Need for batteries and for calibration For oral measurement: pen-shape (can also be used for rectal & axillary measurements) pacifier-shape

3. Infrared thermometers a. Tympanic method: accurate reading of core body temperature (why?) instrument tip inserted into ear canal, measures temp by sensing infrared radiation from blood vessels of eardrum special instruments for that use only + quick (< 5 sec), accurate and simple, can be performed on sleeping child, use of disposable lens covers, noninvasive - relatively expensive, require batteries, routine calibration Not recommended < 6mths old (WHY?) Less than 6 mths old: the ear canal is not fully developed, leading to inappropriate technique and inaccurate readings. Why forehead?

b. Temporal Artery temp. The thermometer detects the natural infrared heat emitted from a subject. Problem with infrared thermometers: need appropriate placement in artery line for accurate measurement, expensive, need batteries The temperature that you read is called "arterial temperature" and is the most accurate of all temperatures, since it comes from the heart. It will usually be close to rectal temperature,

4. Color-change thermometer Contains heat-sensitive material Not accurate

Types of temperature measurement Oral measurement must not be used in patients who mouth-breath, after oral surgery or if patient not fully alert Not suitable for < 3 years old (WHY?) Pacifier-type may be used below this age (but < accurate below 3 months)

Types of temperature measurement Rectal measurement –golden standard (reliable & accurate): Preferred method in children < 6 months insert into rectum: infants > bulb length, children> 1 inch, adults > ½-2 inches Risks: breakage > injury, retention of thermometer, intestinal or mucosal perforation, peritonitis Slow measurement Contraindications: neutropenic patients rectal surgery/injury rectal pathology (e.g. obstructive haemorrhoids, diarrhoea)

Rectal measurement (cont’d) Patient should not be left unattended (changing position may cause thermometer be expelled or broken Relative c/i: neutropenic patient, recent rectal surgery, injury, obstructive hemorrhoids, diarrhea Sources of error: stool impaction & improper technique of measurement

Tympanic measurement Not recommended in infants < 6 months due to not developed ear canal If used properly, is more accurate in adults than axillary or oral

Types of temperature measurement Not routinely recommended Axillary measurement Not recommended routinely (<reliable than oral & rectal routes) recommended for adults who are not candidates for either oral/rectal measurements (e.g. somnolent patients recovering from rectal surgery), children (3mths-5 yrs), children with diarrhoea or severe diaper rash Not reliable for infants and < 3 mths (rectal is preferred) Not reliable with electronic thermometer If fever is detected, it should be confirmed with another method

To ensure reliable measurement: Avoid vigorous physical activity Do not cool or heat oral cavity by smoking, eating or drinking for ~ 20 min. before temperature measurement

Treatment of Fever: Fever is a sign of an underlying process Treatment should focus on the underlying cause instead of temperature reading no correlation between magnitude/pattern of temp elevation (persistent, intermittent, recurrent, prolonged) and the aetiology or severity of the disease Thus, it is difficult to determine the cause of fever based solely on temperature elevation

The main indication for treatment of fever is:  Patient discomfort

Arguments against treatment of fever: The benign and self-limited course of fever The possible elimination of a diagnostic or prognostic sign The untoward effects of antipyretic drugs Fever is not associated with harmful effects unless temperature exceeds 41.1 ° C The attenuation of enhanced host defenses (i.e. possible therapeutic effects of fever)

Arguments against treatment of fever: An evidence: fever is an adaptive response & elevated body temperature maybe beneficial: A. certain microbes may be thermolabile, growth is impaired by higher-than-normal temperature  Clinical evidence: treatment of chickenpox with paracetamol, or rhinovirus with ASA: resulted in longer duration of symptoms than no treatment

B. Low grade fever may also have beneficial effects on host defense mechanisms (e.g. antigen recognition, T-helper lymphocyte function, leukocyte motility) - But these effects have not been shown to favorably alter the course of infectious diseases

Fever is life-threatening if it exceeds 41.1 C People for whom fever may be life-threatening even at lower ranges: Heart problems Pulmonary conditions Infants CNS disorders including tumors Advanced age

Treatment Goals The major goal of self-treatment is to alleviate the discomfort of fever by reducing the body temperature to a normal level General Approach: antipyretic around the clock and continued for at least 24 hours if oral temperature exceeds 38.3 C or causes discomfort or patient is at advanced age nonpharmacologic measures

Exclusions for self-treatment of fever: patients > 3 months old with rectal temperature ≥ 40 ° C children < 3 months old Symptoms of infection impaired O2 utilization (e.g. severe COPD, respiratory distress, heart failure) Impaired immune function (e.g. cancer, HIV) CNS damage (e.g. head trauma, stroke) Children with Hx of febrile seizures or seizures

Non-pharmacologic: light clothing, remove blankets, room temp (25.6° C) increase fluid supply (by at least 30-60 mL/hour in children & by 60-120 mL/hr in adult, unless c/i) if > 40° C- sponging with tepid water, 1 hour after antipyretic intake Should follow oral antipyretic intake by 1 hour (why?) Not recommended if t<40 °C (why?)

Self-reading: What is the maximum duration for pharmacological treatment of fever without referral to a physician? Patient education for fever

Treatment of Fever: children predisposed to seizure: The doctor should be contacted at the 1st sign of fever Antipyretic should be given every 4 hours with one dose during the night Anticonvulsants given by the doctor If febrile-seizure occurred  sponge with tepid water