External Analgesic Products

The Gate-control theory of pain

The Gate-control theory of pain

How the theory of chronic pain works…. The brain commonly blocks out sensations that it knows are not dangerous, such as when the feel of tight-fitting shoes that are put on in the morning has all but vanished by the second cup of coffee…

Mechanism of Muscular Pain Perception

The Gate-control theory of pain:- Neural mechanism in the spinal cord acts like a gate that controls transmission of pain impulses to the brain integrate and evaluate as pain

- Pain signals are carried from pain receptors to spinal cord via 2 types of nerve fibres:

1. Small un-myelinated fibres (C type)2. Large-myelin containing fibres (A delta type)

Mechanism of Muscular Pain Perception

1. Type C- fibres: conduct impulses slowly, associated with dull, aching and lingering pain

2. A-delta fibres: linked with immediate pain, which is sharp and precise with pricking sensation.

Small and large fibres can oppose each other mild stimulation of the large fibres can attenuate pain felt from activation of small fibres MOA of topical counterirritants (e.g. sport-related knee injury)

Types of Musculoskeletal pain

Overuse Injuries Soft Tissue Injury Arthritis Lower Back Pain Other types of Muscular Pain

Types of Muscular pain Overuse injuries:- skeletal muscle pain that is quite

common in persons who are not accustomed to strenuous exercise

- Such injuries result from equal and opposite reactions:1. Macrotrauma

2. Microtrauma

Overuse Injuries Trauma comes in two varieties:

Macrotrauma: sudden catastrophic injury, occurs when an equal and opposite force exceeds the inherent tensile strength of a body structure (e.g. bone, tendon, ligament, muscle) causing the structure to collapse. E.g. falls and sport injuries

Microtrauma: microscopic subclinical injury, results from repeated activity that, over a period of time, overwhelms the tissue’s ability to repair itself- described as: “overuse syndrome”- repetitive microtrauma > break-down structure (e.g. nerve, bursae etc.)- Most commonly encountered in form of tendi/onitis

Overuse Injuries1. Tendinitis Results from strain or injury of tendons Often seen at times of maximum

physical effort (e.g. athletic competitions)

3 phases: inflammation excessive proliferation of CT chronic inflammation (CT overgrowth + tendon degeneration) rupture

Common sites: Achilles tendon (most common injury in sports), shoulder, biceps (football; baseball), patellar-kneecap (volleyball, basketball players)

Example: Carpal tunnel syndrome

Tingling or numbness of the first digits of hands caused by repetitive use of hands and wrists.

Tendon sheets become inflamed which constricts median nerves in the tunnel between the wrist bones

Overuse InjuriesFactors contributing to producing an overuse injury

In industry Poorly designed equipment Awkward working position Lack of job variation Long working hours Inadequate rest breaks Bonuses for overtime

Overuse InjuriesFactors contributing to producing an overuse injury

In athletics Age Poor technique Exercise of prolonged intensity/duration Poorly designed equipment (e.g. shoes)

Fluoroquinolones > associated with tendon repture> FDA warning! (what is it?)

Overuse Injuries2. Bursitis Definition: Bursae Overuse trauma (either friction or external

pressure) inflammation with fluid build-up. Localised pain, tenderness and swelling Pain acute: macrotrauma or microtrauma

chronic: infection (Dx: by aspiration of fluid)

Symptoms can mimic arthritis pain (how to distinguish?)

Bursitis vs. arthritis Location:

bursae within joints (knee, shoulder and big toe; weight bearing joints (knee, hips, low back, hands)

Signs: warmth, edema, erythema, and possible crepitus; noninflmmatory joints, narrowing of joint space, restructuring of

bone and cartilage and possible swelling Sx:

Constant and worsens with movement or application of pressure over the joint;

dull joint pain relieved by rest, joint stiffness < 20-30 minutes, localized symptoms to joint

Bursitis vs. arthritis Onset:

acute with injury, recurs with precipitant use of joint;

insidious development over years Exacerbated by:

movement of affected joints; obesity, lack of activity or heavy

physical activity, repetitive movement and trauma

Bursitis

Overuse Injuries3. Occupational Repetition Strain: Muscle and tendon injuries of the upper

limbs, shoulders and neck. Due to overload on particular muscles

(due to awkward working positions or repeated use) Overload pain, fatigue, decline in work

performance The most likely candidates:

- Assembly line workers- Typists

“the new industrial epidemic”

“the new industrial epidemic”

Soft Tissue Injury A sprain is a partial or complete

rupture of a ligament A bruise is a rupture of tissue resulting

in haematoma A strain is a partial tear of muscles

Soft Tissue Injury Sprains

Strains:- occurs mostly during forceful muscle action- occurs soon after an activity has begun (e.g. when race has just started)- muscle: sore, painful, movement difficult

joint being forced beyond its normal range of motion (e.g. hyper-extended knee)

Joint forced in a plane through which little or no motion actually exists (e.g. lateral ankle sprain)

Arthritis Joint pain may be caused by either

rheumatoid arthritis (RA) or osteoarthritis (DJD)

Endogenous neuropeptides (e.g. substance P) are involved in the pathogenesis, the inflammation and cartilage destruction in both diseases

Lower Back Pain 70% at least once in their lives Primarily: due to sedentary life style,

(particularly the one disrupted by bursts of activity)

Poor posture Improper shoes Excess body weight Poor mattress and sleeping posture Improper technique in lifting heavy objects

injuries

Lower Back Pain In addition to injuries, causes of

backache includes:1. Congenital anomalies

2. Osteoarthritis

3. Spinal tuberculosis

4. Referred pain from kidneys, pancreas, liver or prostate

Other Types of Muscular Pain Acute, temporary stiffness and muscle

pain can result from: cold, dampness, rapid temperature changes or air currents

Sometimes, referred pain in the skeletal muscles of the shoulder may result from:

Cardiovascular Disease (e.g. angina pectoris)

Gastrointestinal complaints (e.g. gallbladder or oesophagus)

Patient AssessmentPharmacists should enquire about: Duration and type of pain

if pain > 7 days underlying serious condition??

Cause of painmuscular/joint pain caused by overexertion valid indication for OTC ext. anal. Use

Severity/location of pain

If mild, located OTC ext. anal. Otherwise, may be referred from viscera OTC X X

X

Patient AssessmentIf the pain is in the joint

Is joint red, swollen, warm and tender to the touch???

May be a fracture or rupture in ligament or tendon and/or arthritic involvement

NO YES

OTC ext. anal.

X X X OTC would delay an accurate Dx see Dr.

Treatment/Non-pharmacologic

Usually 1-2 days

ASAP; 10-15 min. tid to qid (1-3 days)

2-3 hours/d

Treatment/pharmacologic

External analgesics (Definition)1. Local anaesthetics;2. Local analgesics;3. Local antipruritics;

4. Counterirritants

Depress cutaneous sensory receptors for pain, burning and itching.

act directly on skin to diminish symptoms result from cuts, abrasions, insect bites etc.

Treatment Counterirritation: the paradoxical pain-relieving

effect achieved by producing less severe pain to counter a more intense one.

Relieve pain indirectly by stimulating cutaneous receptors to induce sensations such as cold, warmth or sometimes itching

These induced sensations distract from deep-seated pain in muscles, joints, tendons etc., which are distant from skin, where counterirritant is applied.

Some counterirritants effect dose dependent (e.g. menthol)

Counterirritants Menthol if < 1.0% depress receptors

> 1.25% stimulate receptors The intensity of response to counterirritant

depends on the irritant used, its concentration, the solvent used and duration of its contact with skin

Increased risk of irritation, redness or blistering with tight bandaging or occlusive dressing

Their action has strong psychological component

Rubifacients are counterirritants that cause vasodilatation of cutaneous vessels

Analgesics, Anaesthetics & Antipruritics

Act by overcoming stimulus that causes pain

Must be percutaneously absorbed first Same action as internal analgesics Their effect is systemic in nature Relieve any deep-seated pain,

provided their interstitial fluid concentration is sufficiently high

Pharmacologic Agents

Classification of OTC counterirritant external analgesics (Category I)

Group

Characteristics Ingredients Conc. (%)

A Induce redness and irritation, more potent than other used C/I

AllylisothiocyanateAmmonia waterMethyl salicylateTurpentine oil

0.5-5.01.0-2.510-606-50

B Produce cooling sensation, have strong organoleptic properties

CamphorMenthol

3-111.25-16

Classification of OTC counterirritant external analgesics (Category I)

Group

Characteristics Ingredients Conc. (%)

C Cause vasodilatation

Histamine dihydrochlorideMethyl nicotinate

0.025-0.1

0.25-1.0

D Incite irritation without rubefaction; are equal in potency to group A ingredients

CapsicumCapsicum oleoresinCapsaicin

0.025-0.25SameSame

Counterirritants (Group A)

Allylisothiocyanate “essence of mustard”

Derived from seeds of black mustard plant In high concentration (or if applied for a long

period of time) Absorbed rapidly from intact skin and mucous membranes ulceration if not removed soon after application

“Mustard Plaster”: home remedy Should never be inhaled/tasted

undiluted toxic

Counterirritants (Group A)

Stronger Ammonia Water If not diluted caustic vapour

Sneezing, coughing

In concentration: pulmonary oedema

Asphyxia because of glottis spasm

Eye irritation

•Weeping

•conjunctival swelling

•temporary blindness

- Should be handled with care and never inhaled.- Dilute before use

Counterirritants (Group A)Methyl Salicylate “wintergreen oil”

The most widely used counterirritant. At v low conc. used as flavouring agent/aroma in

candies, chewing gum, toothpastes etc Ingestion of more than small amounts in hazardous

because of the high salicylate content. Liquid preparations of > 5% child-resistant containers Avoid using with heat or after strenuous exercise (why?)

Caution is patients allergic to ASA, having asthma or nasal polyps

Counterirritants (Group A)

Turpentine Oil Prepared from Turpentine oleoresin collected

from pine trees As an irritant: acts by defatting the skin causing

dryness and fissuring May cause eczema for sensitive skin Systemic absorption may cause GIT upset, skin

and respiratory symptoms in susceptible people Ingestion can be fatal (15mL in children and 140mL in

adults)

Counterirritants (Group B)

Menthol Obtained either from peppermint or synthetically In small quantities flavouring agent in candies,

chewing gums, cigarettes Dose dependent effect: < 1.0% depress receptors

> 1.25% counterirritant

Some patients may have reactions to menthol: wheezing, urticaria,erythema, contact dermatitis

Counterirritants (Group B)

Camphor Obtained either from camphor tree or

synthetically Dose-dependent effect:

< 3% topical analgesic, anaesthetic, antipruritic>3% counterirritantif applied vigorously rubefacient action

Concentrations >11% are unsafe and toxic if ingested.

Counterirritants (Group C)

Histamine Dihydrochloride Histamine: causes vasodilatation

is also absorbed percutaneously

Counterirritants (Group C)

Methyl Nicotinate This ester has a marked power to penetrate the

cutaneous barrier In a very low concentrations, ~ causes vasodilatation

and elevation of temperature Indomethacin, ibuprofen and ASA significantly

reduces the skin’s vascular response to ~ conclusion?

If applied over large areas drop in BP, pulse rate and syncope due to generalised vascular dilation.

Vasodilatation response due to ~ is mediated at least in part by prostaglandin biosynthesis

Counterirritants (Group D)

Capsicum Preparations 1 Capsicum Capsicum oleoresin Capsaicin Are derived from the fruit of various species of

plants of the nightshade family The major compound is capsaicin, which is also

the major ingredient in the hot (chile) pepper Elicits transient feeling of warmth In high concentrations burning pain which will

rapidly diminish due to tachyphylaxis

Counterirritants (Group D)

Capsicum Preparations 2

DO NOT CAUSE reddening or blisters even at high conc. (WHY??)

Capsaicin depletion of substance P from sensory neurons that have been implicated in mediating cutaneous pain

Substance P

Because they do not work on blood vessels

pain

vasodilatation

Pruritic stimuli

XXX X= capsaicin

effect

Counterirritants (Group D)

Capsicum Preparations 3

Because it depletes substance-P, capsaicin has an increasing role in the treatment of:

1. Postherpetic neuralgia2. Psoriasis3. Post mastectomy pain4. Reflex sympathetic dystrophy5. Diabetic neuropathy (e.g. alleviate aching and burning

foot pain)

Combination Products Two or more safe and effective ingredients

(category I) may be combined: (1) when each active ingredient contributed to the claimed effect & (2) if this combination does not decrease the safety or effectiveness of any individual active ingredient

It is irrational to combine counterirritants with local anaesthetics, topical antipruritics or topical analgesics (WHY?)Because these agents depress sensory cutaneous receptors which opposes the effect of counterirritants.

=Methylsalicylate+ turpine oil+menthol

Dosage FormsFinished product= active ingredient(s)+ vehicle The ideal topical drug vehicle should be:1. Easy to apply and remove2. Nontoxic, nonirritating and nonallergenic3. Cosmetically acceptable, nongreasy &

nondehydrating4. Homogenous5. Bacteriostatic6. Chemically stable7. Pharmacologically inert8. Keep skin penetration to a minimum

Dosage Forms

Liniments: solutions or mixtures of various substances in oil, alcoholic solutions of soap, or emulsions.

Applied by friction or rubbing (the oil, soap base facilitates massage)

The vehicle selected in basis of desired action:

Alcoholic/hydroalcoholic vehicle when rubefacient or counterirritant action is desired

Oleoginous vehicles are used when massage is required

Dosage Forms

Gels: generally clear, composed of water-soluble ingredients and are of more uniform and semisolid consistency

Provide greater sensation of warmth than lotions or ointments (gels promote more rapid and extensive penetration of medication into skin and hair follicles)

Excessive amounts or rubbing should be avoided (WHY?) because increased penetration may cause an unpleasant burning sensation

Dosage Forms

Lotions: suspensions of solids in an aqueous medium, applied to skin without friction for the protective or therapeutic value of their constituents

Intended to dry on the skin after application Fluidity uniform and rapid application over wide

areas especially suited for hairy body areas Should be shaken before each use (WHY?)Because suspensions tend to separate while standing

Dosage Forms

Ointments: semisolid preparations particularly desirable for counterirritation because they are applied with massage (just like liniments)

Clinical Consideration:- oil/water formulations are preferred for day

time use (because they are washable from skin)

- Protect clothing with a cover but not tight (irritation, reddening and blistering)

Non-drug Measures 1

1. Heat: The most frequently used Heat lamp Hot water bottle Heat pad Moist steam pack

- After a stretch injury, collagen does not return to its resting length…

Non-drug Measures 2 Heat: 1. Helps to restore the elastic

properties of collagen by increasing the viscous flow

2. Increases threshold in free nerve endings analgesic effect

However, heat should not be used simultaneously with counterirritant preparation (WHY?)Severe burning, blistering, skin necrosis and interstitial nephritis

Non-drug Measures 2

2. MassageIncreases flow of lymph and blood in skin and underlying structures > warmth>same effect as heat

Patient CounsellingPrecautions: For external use only D/C if condition worsens or last > 7 days Don’t apply to open wound or broken skin Don’t apply with tight bandage Wash hands thoroughly after application Do not handle or insert contact lenses following

application without washing your hands Don’t apply to children < 2 years old