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Pain
Compound analgesics and
the management of pain
Prof CL Odendaal
Department of
anaesthesiology
University of the Free State,
Bloemfontein
Introduction
Despite advances in modern medical and
supplementary therapies, the numbers of
patients who are suffering from pain are
still very high.
Albert Schweitzer once said: “We must
all die. But that I can save him from days
of torture, that is what I feel as my great
and ever new privilege. Pain is a more terrible lord of mankind than even death itself.”
The definition of pain as defined by the
International Association for the Study of
Pain (IASP) involves sensory and emotional experiences, with or without actual
tissue damage.
In modern surgery we all strive to
achieve ‘balanced anaesthesia’ but the
concept of ‘balanced analgesia’ has also
been propagated. Possibly this concept
led to the development of the ‘multi-substance analgesics’ or ‘multi-compound
analgesics’ that have overflowed the markets in SA. SA has the highest number of
multicompound analgesics in the world,
and it must be asked if this is good or bad.
Goals of treating pain
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Initiate the safest, simplest, most cost
effective therapy
Multiple substance therapy is at the same
time a ‘shotgun’ approach and makes it impossible to evaluate an individual therapy
aimed at safety and efficacy
Therapeutic goals must be education and
determination to achieve minimisation of
pain
Treat but do not over-treat.
What do we want to achieve?
The objective of treating pain is to have the
concentration of the substance varying in the
therapeutic window of the body (see Figure 1).
The Specialist Forum | September 2012
Figure 1
This is easily obtained in post-operative pain
by using a PCA-apparatus where the patient
controls his/her own pain by pressing a button. However, it is also possible to maintain an
effective blood concentration by administering the drug orally at specific time intervals e.g.
four hourly, six hourly or eight hourly for 24 or
48 hours. Reassess the situation again and if
not effective, change either the time interval or
the dose for the next controlled period.
When the concentration goes above the line,
side effects will occur or below the line, it will
be ineffective.
Classification of pain
Pain is usually classified as acute, chronic and
cancer pain. It can be also be classified as nociceptive pain or neuropathic pain, which will
make pharmacological treatment more understandable.
Nociceptive pain occurs when there is tissue
damage with the release of the so-called ‘inflammatory soup’. The release of these substances either stimulate the free nerve endings directly or indirectly through the action
of mediators on the nociceptors. Important
here is that the pain pathways in these types
of pain are intact. Conduction of impulses is
usually through the fast tracts or Ad fibres and
also by, to a certain extent, the c-fibres.
For the treatment of such pain, one should
adhere to the basis of the WHO Analgesic ladder. Stuck to the principle of the ladder, pain
can be effectively treated in 80-90% of pain
sufferers.
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Pain
Compound
analgesics and
the management
of pain
Neuropathic pain is a type of pain in which
there is definite dysfunction or damage to the
pain pathways. These are usually conducted
by c-fibres. Ordinary analgesics and NSAID’s
have little or no effect. This type of pain is usually treated with the first generation antidepressants e.g. amitryptaline or the anticonvulsants e.g. carbamazepine or lately the
GABA-agonists, gabapentin or pre-gaballin.
Pathophysiology of pain
Pain is caused by the stimulation of free nerve
endings called nociceptors. Nociceptors present as:
• Somatic nociceptors - in the skin and connective tissue
• Visceral nociceptors - intra-abdominal or
pelvic tissue.
Nociceptors may be stimulated by:
• Physical stimuli - pressure, heat or visceral
distension
• Chemical stimuli - due to tissue damage or
inflammation.
Tissue damage results in the production and
accumulation of algesic substances which
have been shown to affect nociceptors. Such
substances are prostaglandins, bradikinin,
serotonin, histamine, potassium and hydrogen ions.
Figure 2
Stimulation of these nociceptors causes impulses to be carried along the peripheral
nerve to the Wide Dynamic Range cells in the
dorsal horn of the spinal column. In the dorsal
horn, a synapse is formed with cells of the
spino-thalamic tract. They carry impulses up
the spinal cord, through the brain to the thalamus where the next synapse is formed. From
the thalamus, impulses are delivered to several areas of the cerebral cortex where ‘pain’ is
interpreted.
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The dorsal horn is the major site of pain
modulation. This is the site where the mechanism of the ‘Gate-theory’ by Wall and Melzack
is applied. This is a complex system of interneurons which may be inhibitory or facilitatory. The inhibitory neurons have endorphins
as neurotransmitters. Facilitatory neurons
have sP (substance P) as neurotransmitter.
Too often patients are labelled as neurotic,
hysterical or over-reactors because of the lack
of understanding of pain and realising that
there is a scientific basis for individual variation in the perception of pain.
Figure 3
Treatment regimens
Pain should be treated starting with the first
step of the ladder or basic substance e.g.
paracetamol. Dosage: 300-1000mg every 4-6
hours. Daily dose should not exceed 4-6g per
day.
If that isn’t successful, a NSAIM or a weak opioid could be added. Best example of this is a
combination of paracetamol + codeiene; a
very effective analgesic. Dosage: paracetamol
450 mg + codeine 30 mg. Dolorol Forte.
A still stronger analgesic could be the combination of the three steps above e.g. paracetamol, codeine and ibuprofen.
Here we have a
• Central-acting drug: paracetamol;
• m-receptor-agonist: codeine
• peripheral acting drug: NSAIM viz ibuprofen.
The above-mentioned combinations are
logical and very effective. Any pain caused by
tissue damage can be treated with this in
mind.
Pharmacology
Paracetamol
Central acting analgesic and antipyretic drug
used for mild to moderate pain.
The mechanism of action of paracetamol still
remains unresolved. The greater sensitivity of
cells containing COX-3 to paracetamol is currently accepted as the action of paracetamol.
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Compound
analgesics and
the management
of pain
It was shown that paracetamol inhibits neural
cells that have a low synthesis rate and containing low levels of peroxide. It appears that
when arachidonic acid levels are low paracetamol acts as a specific COX-2 inhibitor. Thus
paracetamol has predominant effects on cells
in the CNS because peroxide levels and arachidonic levels are lower than in the peripheral
tissues where an inflammatory process may
be going on.
Although it has been accepted as a safe analgesic, the incidence of hepatic toxicity has
risen during the past few years due to over
dosage. This happens as a result of ingesting
5-8g daily over an extended period of time.
Side effects:
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anorexia
nausea and vomiting
later jaundice
increase in AST and ALT liver enzymes.
Drug interactions
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Favourable with NSAIDs and opioids works synergistically.
Non-steroid anti-inflammatory drugs
These drugs are used regularly alone or in
combination with other analgesics. The effects of these drugs are as follows, and may
appear in a more or lesser degree with all the
NSAIDs.
• These drugs alter the nociceptive response caused by bradykinin
• Inhibit prostaglandin E synthesis
• Have a direct analgesic action on higher
centres
• Reduce platelet aggregation
• May cause hypoprothrombinaemia
• Reduce body temperature in low dosages
• Reduce blood sugar concentrations.
• Induce acid-base imbalance and acidosis.
Included in the group are: lornoxicam (Xefo®),
indomethacin (Indocid®), ibuprofen, diclofenac (Voltaren®).
These agents are used mainly for treatment
of skeletal pain. Selective COX-2 inhibitors
(Celecoxib, Etoricoxib) inhibit only the COX 2
enzyme thus have less side effects on platelet
and renal function.
Codeine
This is an opiate with the same m-receptor
action as morphine. Its action is approximately 10% of that of morphine. It is extremely well absorbed orally. It is used in mild
to moderate pain.
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Side effects
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Serious additive effects with phenothiazines, tranquilisers, sedative-hypnotics,
alcohol
Respiratory depression, hypotension, profound sedation with over-use
Dependency.
Combination drugs
The main reason for development of combination drugs is to gain efficacy, reduce toxicity,
interact pharmaco-kinetically and dynamically or both, positively or negatively. Thus,
combinations should display either additive
or synergistic analgesia in which a lower dose
of each substance should increase efficacy
without harm to the patient. 1
Combinations in all literature are aimed at
analgesic receptors only i.e.:
• opioids - μ receptors
• paracetamol - central PGE3
• NSAIDs - peripheral
• Tramadol - partial opioid + antiserotonin
and noradrenaline inhibitor effects.
Until recently only a few oral combinations
were approved in US by the FDA containing
only opioids and/or NSAID’s i.e. ibuprofen and
hydrocodone.
The WHO recognise the efficacy of combinations and based on extensive evidence of the
200 top prescribers only nine opioid/acetaminophen/NSAID combinations were recommended by WHO for treatment of moderate severe pain.
SA is the country with the most multi-substance analgesics in the world. It contains
analgesics and many other substances.
Almost every firm produces its own version of
‘the best analgesic’.
There are 89 different multisubstance analgesics in SA.These tablets/capsules contain a
wide variety of substances that have nothing
to do with management of pain i.e. antihistamines. The question can therefore be asked: is
this ‘the good, the bad or the ugly?’
No single analgesic is perfect and no single
analgesic can treat all types of pain. Yet each
agent has distinct advantages and disadvantages compared to others.2
Already in 1998 it has been stated that many
of the combination analgesic preparations
available in South Africa are patently irrational,
that their efficacy as analgesics is suspect, that
their potential toxicity is great, and that a potential for abuse exists because of their `psychic cocktail’ constituents.3
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Compound
analgesics and
the management
of pain
Rational combinations of analgesic drugs
offer a viable approach to managing persistent pain that involves multiple sites or pathways.4
Pharmacology of substances
used in combination drugs in
South Africa
Propoxyphene
This drug has now been banned in most of the
countries of the world. In South Africa there
was also huge outcry. The case still continues.
Propoxyphene is a relatively weak opioid.
The weight of evidence to the recommended
doses of propoxyphene states that it is no
more and probably less effective than the
usual doses of paracetamol, aspirin or any
other NSAID.
Bearing this in mind, it must be appreciated
that the adverse effects are dose dependent
and as far as for the other opioid analgesics,
include the risk for dependence and abuse.
Over dosage is a serious problem and has
proved fatal.
Overdose causes respiratory depression and
cardiac dysrhythmias. Accumulation of an active metabolite has local anaesthetic effects.
DXP is a more potent LA than propoxyphene,
and is more potent than lignocaine. It is this
metabolite that is responsible for cardiac dysrhythmias because of its potent cardiac membrane and Na+ channel blocking effects. It has
the characteristics of Vaughn-Williams, class
1c classification. It is also not reversible by
naloxone.
Most dangerous aspect of DPX is the active
metabolite - norpropoxyphene which is highly
cardiotoxic; it blocks both IK & hERG channels
(K+), leading to QT interval prolongation, leading to torsade des pointes and sudden death.
It is doubtful that propoxyphene
hydrochloride 65mg provides an
analgesic effect equal to that of
650mg aspirin
In a critical analysis of information on
propoxyphene that has been published since
the drug’s introduction, the following conclusion has been reached: It is doubtful that
propoxyphene hydrochloride 65mg provides
an analgesic effect equal to that of 650mg aspirin. There is no conclusive evidence that
combinations of propoxyphene with other
analgesics are more effective than
propoxyphene alone or even other analgesics
alone.
Caffeine
Caffeine is a methylxanthine structurally related to theophylline. It is a stimulant and has
been used to restore mental alertness and
wakefulness. It is well absorbed from the gut
with peak levels occurring within 15-45 minutes. Elimination half-life is approximately 3-5
hours.
It is also recognised as an effective analgesic
adjunct. There is some evidence that IV caffeine sodium benzoate or even oral caffeine
preparations may have some efficacy in the
treatment of PDPH.
Side effects
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Gastrointestinal disturbances
Nervousness
Diuresis
Irritability
Dysrhythmias, tachycardia and palpitations
Tremulouses
Muscle twitching.
Meprobamate
Carbamate derivative. Used as anxiolytic.
Doses: 1.2-1.6g per day given in 3-4 divided
doses. Elimination half-life is 6-18 hours.
Serum concentrations in excess of 12mg/dl
are associated with coma.
Meprobamate has been reported to have
some muscle relaxant properties with associated pain relief in the treatment of musculoskeletal symptoms. However, many reports
have indicated that other agents are much
more effective in the treatment of these symptoms.5
Adverse effects
Propoxyphene interacts with several other
drugs through inhibition of liver enzymes and
there have been occasional reports of jaundice with its use. Fatal interactions are with
carbamazepine and alcohol in normal dose
range.
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Thrombocytopenia
Leucopoenia
Agranulocytosis
Hypotension
Drowsiness
Dizziness
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analgesics and
the management
of pain
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Vertigo
Seizures
Blurred vision
Cutaneous reactions.
Most serious side effect is the potent addiction potential with marked withdrawal reactions. This makes it a dangerous drug.6
Phenyltoloxamine/
diphenhydramine
Effective antihistaminic drugs. Although
phenyltoloxamine has been associated with
independent analgesic activity and adjuvant
analgesic effects in combination with acetaminophen, the benefits achieved with the
drug in most were minimal and of questionable clinical importance.7 The conventional
combination of phenyltoloxamine/acetaminophen 60/650 mg offers no advantage
over maximal doses of acetaminophen alone
(1g). As a matter of fact, in a study of post-oral
surgery patients, the combination as mentioned above was less effective than acetaminophen alone. Improvement seen with its
use may be due to the sedative effects in settings where anxiety or tension is a component
of the pain picture.
Side effects
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Drowsiness
Dizziness
Gastrointestinal disturbances
Blurred vision
Tachycardia
Diaphoresis
Atrio-ventricular heart block.
Orphenadrine
Indicated for relief of pain associated with
acute musculoskeletal conditions. With the
addition of acetaminophen 450mg and orphenadrine 35mg tds effective analgesia was
encountered in myalgia secondary to tension
of the cervical and upper thoracic muscle
spasm.
It should be used alone and no other analgesics added.8
Adverse effects
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Light headedness
Syncope
Dizziness
Mental confusion
Drowsiness
Hallucinations
Agitation
Tremor
Dependence (Shariatmadari, 1975).
Combination therapy
Combinations of drugs with different analgesic properties. Literature reports confirm
beneficial effects with opioid/NSAID combinations.
• Fewer opioid dosages
• Reduced opioid requirements
• Shorter duration of post-operative opioid
therapy
• Significant increases in analgesic potency
• Combinations more effective than single
agents alone
• Reduced adverse effects.
Combinations with other substances
The multi-substance combinations are sometimes totally illogical and include substances
which have no proven benefit. These compounds may be harmful and can worsen the
patient’s condition. The most often used
drugs include pemoline, propoxyphene,
meprobamate, caffeine and diphenhydramine. Diphenhydramine is known to delay
absorption of other orally administered
drugs.9
Conclusion
We should seriously rethink our management
of pain - acute/chronic. The prescription
should be scientifically and pharmacological
correctly worked out. Most importantly
always keep side effects in mind.
I am not asking you to stop prescribing. I am
asking you to think about what you are giving
your patient. Do you know what the effects
are? Do you know what the side effects are?
Hippocrates, the father of medicine said,
“Above all, do no harm.” Remember, no drug in
the world is free of side effects, even the ‘doctor’s friend’. Be careful.
References
1. Raffa RB, Pergolizzi JV, Tallarida RJ. “The determination and application of fixed-dose analgesic combinations fot treating multimodal pain. The Journal of Pain; Vol11; No 8, 2010. 701-709
2. Raffa RB, Pharmacology of oral combination analgesics: rational
therapy for pain. J of Clin Pharmacy and Therapeutics. 2001, 26,
257-264
3. Truter I; “An Investigation into Compound Analgesic Prescribing
in South Africa, with special emphasis on Meprobamate-containing Analgesics. Pharmacoepidemiology and Drug Safety; 7:
91-97 (1998)
4. Raffa RB, Clin Rheumatol; 2006, 25 (Suppl 1): S9 – S15
5. Winkelman & Richards, 1975
6. Truter I; “An Investigation into Compound Analgesic Prescribing
in South Africa, with special emphasis on Meprobamate-containing Analgesics. Pharmacoepidemiology and Drug Safety; 7:
91-97 (1998)
7. Raffa RB; Antihistamines as analgesics. J of Clinical Pharmacy and
Therapeutics; 2001; 26, 81-85
8. Hoivik & Moe, 1983
9. Raffa RB; Antihistamines as analgesics. J of Clinical Pharmacy and
Therapeutics; 2001; 26, 81-85
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September 2012 | The Specialist Forum