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Opioid analgesics - A 2018 update

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Opioid analgesics – a 2018 update

Schellack G, BCur, Adv Univ Dipl Nurs Sc (HSM), Hons BSc (Pharmacology), Clinical research specialist in the pharmaceutical industry
Schellack N, BCur, BPharm, PhD (Pharmacy), Associate Professor*
Meyer JC, BPharm, MSc (Med) Pharmacy, PhD (Pharmacy), Associate Professor*

*School of Pharmacy, Sefako Makgatho Health Sciences University (SMU)

Correspondence to: Prof Natalie Schellack, e-mail: [email protected]

Keywords: pain, opioid, morphine, codeine, oxycodone, hydromorphone, buprenorphine, pain ladder, tapentadol

Abstract
The opioid analgesic drugs constitute one of the most important groups of pharmacotherapeutic agents in the clinical practice setting.
They are vital to pain management, especially moderate to severe cancer and visceral pain, in a myriad of healthcare settings. The key
to optimal pain management is the ability to effectively manage patients to ensure optimal pain relief, whilst also minimising or
managing the side-effects of their pain medication. This necessitates effective collaboration between all the healthcare professionals
managing the patient. This article provides an updated overview of the opioid analgesics, and their usefulness in clinical practice.
© Medpharm S Afr Pharm J 2018;85(1):43-49

Introduction true opioid peptide receptors, but they do explain many

of the unwanted effects of some opioid analgesics, such as
As a class, the opioid analgesics are arguably one of the most
pentazocine).
important groups of pharmacotherapeutic agents in the clinical
• Nociceptin opioid peptide (NOP) receptors have also been
practice setting. These drugs are either related to morphine
identified; these are G-protein-coupled receptors for the
in structure and action, or they are synthetic derivatives with
endogenous opioid-like ligand known as nociceptin or orphanin
different chemical structures. Morphine is the most important
FQ, which does not seem to display any affinity towards the
of the opioid analgesics. It is a plant alkaloid (i.e. an organic base
MOP, DOP, or KOP receptors (naloxone also does not act as an
substance, which is found in, and extracted from, plant material)
antagonist at these receptors).
that is extracted from the wild opium poppy, Papaver somniferum.
A second alkaloid, codeine, is extracted from the same plant. The neurotransmitters that act on these receptors include:
Codeine and morphine are classified as phenanthrenes (opioid endorphins (especially β-endorphin), dynorphins, enkephalins
alkaloids that act as narcotic analgesics). The benzylisoquinolines (e.g. leu- and met-enkephalin), and other endogenous opioid
are alkaloids that do not display the typical effects of the opioid peptides.1
analgesics. Papaverine acts as an antispasmodic and noscapine
The most significant physiological effects of these
as a cough suppressant. The opioid analgesics suppress the
neurotransmitters are seen within the central nervous system
neurotransmission of pain sensations due to their primary action
(CNS), and may be summarised as follows1-4:
in the spinal cord and brain (i.e. where their supraspinal receptors
• The opioid peptides act as inhibitory neurotransmitters within
are located). They are the drugs of choice in the management of
the CNS. Opioid receptors are found throughout the brain,
visceral and severe pain.1
especially in the limbic system, as well as the brain stem and the
The opioid peptides and their receptors posterior (dorsal) horn of spinal cord grey matter.
(µ, δ, κ and σ) • Some notable CNS functions, which are influenced by these
receptors, are: emotions and the processing of pain stimuli (the
The following receptors are utilised by the endorphins, dynorphins, emotional aspects of pain perception), mood and consciousness.
enkephalins and other endogenous opioid peptides, with their Stimulation of these peptide receptors may also suppress brain
subtypes1-4: stem functions such as coughing and respiration.
• Mu- (µ) and delta- (δ) receptors, also referred to as the mu opioid • All the receptor-subtypes are present within the CNS.
peptide (MOP) and delta opioid peptide (DOP) receptors.
• Stimulation of the µ, δ and κ-receptors will result in a decrease in
• Kappa- (κ) receptors, also referred to as the kappa opioid the concentration of cyclic adenosine monophosphate (cAMP),
peptide (KOP) receptors. will inhibit the opening of calcium-channels, and facilitate the
• Sigma- (σ) receptors (σ-receptors are not considered to be opening of potassium-channels.

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Mu- (µ) and delta- (δ) receptors Opioid analgesia

These two receptor subtypes closely resemble one another in their Across the globe, millions of people with cancer and other disease
functionality. A huge problem with opioid analgesics, however, is states experience moderate to severe pain, many without access
tolerance (especially in chronic pain management and chronic to adequate treatment. These people face severe suffering for
months on end, and eventually die in unnecessary agony due to
care settings).1 According to Sommers,5 patients who develop
pain, which is almost always preventable and treatable.6,7 Many
tolerance to the analgesic effects of mu-receptor agonists could
developing countries lack the necessary economic, human and
still obtain satisfactory levels of pain relief with delta-receptor logistic resources to provide optimal pain treatment to their
stimulation. population.6

There are at least two important mu-receptor subtypes1-4: Pain is defined as “…an unpleasant sensory and emotional
• µ1-receptors: These receptors are involved in the analgesic and experience associated with actual or potential tissue damage
or described in terms of such damage”.8 Pain is one of the most
euphoric effects of the opioids and are found in the CNS.
prevalent and most feared symptoms in patients with cancer and
• µ2-receptors: These receptors are found in the CNS, where other non-malignant diseases. Hence, good pain management is
they are implicated in the respiratory depression caused by the one of the central pillars of good patient care.9
opioid analgesics, and also peripherally in the GIT, where they
The World Health Organization’s (WHO) analgesic ladder serves
cause constipation. as the mainstay of treatment for the relief of pain, combined
with the relevant and necessary psychological and rehabilitative
The delta-receptors are also of importance in peripheral tissues.
modalities.10 This multidimensional approach offers the greatest
Further subtypes of these receptors, as well as subtypes of the
potential for maximising the effectiveness of analgesia, whilst
kappa- and sigma-receptors, also exist.1 minimising the adverse effects thereof. According to literature,
Effects of opioid peptide receptor stimulation about 70–90% of cancer pain is relieved when clinicians apply the
steps of the WHO’s pain ladder appropriately.10 According to the
Table I gives an exposition of the most significant effects that WHO,11 the key to effective pain management is contained in the
stimulation of the opioid receptors have on nervous system following principles:
functioning. It also highlights the usefulness and some of the • By mouth: If possible, analgesic should be given by mouth.
expected side-effects of the opioid analgesics. • By the clock: Analgesics should be given at fixed time intervals

Table I. The major effects of opioid receptor stimulation1

Mu (µ) Delta (δ) Kappa (κ) Sigma (σ)*
Pain Strong analgesic effects at spinal Spinal analgesic effects Peripheral and some spinal
and supraspinal (brain) level, as analgesic effects
well as peripherally
Mood and consciousness Euphoria, sedation Sedation, dysphoria Dysphoria, hallucinations and
nightmares
Breathing Suppresses the respiratory centre Some respiratory Stimulation, tachypnoea
(also suppresses the cough depression
centre)
Blood pressure and pulse May cause bradycardia Increases blood pressure and
rate pulse rate
Gastrointestinal tract Smooth muscle contraction with Reduced gastrointestinal
spastic paralysis of the small motility
intestine, leading to constipation;
increased biliary sphincter tone**;
also causes nausea and vomiting

Other Miosis, physical dependence Mydriasis, hypertonia

*Not a true opioid receptor.
**The increased tone of the sphincter of Oddi is less pronounced with pethidine (syn. meperidine).
Note: This table only highlights the most prominent effects that are associated with stimulation of each of the listed receptor subtypes.

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and the dosages should be titrated according to the needs • The development of tolerance (tachyphylaxis) to the chronic
of individual patients. Subsequent dosages should be given use of opioids.
before the previous dosage has fully worn off. • Successful pain management with the use of opioid analgesics
• For the individual: The choice of agent and dosages of the may be achieved by balancing the adverse effects with the
selected analgesics should be tailored to the patient. level of analgesia in each individual patient.13 The newer, oral
• By the ladder: The WHO ladder, illustrated in Figure 1, advocates opioid formulations that are available for the management of
the following stepped approach to the use of analgesics11: moderate to severe pain, can assist in achieving effective levels
of analgesia in patients.
Step 1: Non-opioids (e.g. aspirin, paracetamol or ibuprofen) are
used for mild to moderate pain. The opioid drugs
Step 2: Weak opioids (e.g. codeine phosphate, dihydrocodeine, Two major drug groups are utilised in the pharmacotherapeutic
tramadol and buprenorphine), are recommended for moderate management of pain, namely the opioid analgesics for [moderate
pain, used alone or in combination with a non-opioid. to] severe pain, and the non-opioid analgesics that are generally
Step 3: Strong opioids (e.g. morphine, hydromorphone, used in the management of mild to moderate pain.1
oxycodone, buprenorphine and tapentadol (the latter is not
The opioid analgesics may be classified in a variety of ways. In
available on the South African market yet) may be used alone or
clinical practice, however, the most practical classification is based
in combination with a non-opioid for severe pain.
upon the degree of efficacy that may be expected from each
Note: Although the package inserts of certain opioid analgesics one of the more commonly used drugs. Therefore, a distinction
may display a registered indication of “moderate to severe” pain, is made between high-potency agents, low-potency agents, and
the WHO ladder recommends the weaker opioid agents for the opioid agents of intermediate potency. Some authors choose to
former, and the stronger ones for the latter level of severity. refer to high-, low- and intermediate-efficacy agents. Their degree
If, at the initial consultation, the patient’s pain can already be of potency, or efficacy, is dependent on whether they act as full
regarded as severe, it is recommended that the physician move agonists at µ-receptors, since most of the currently available
to the third level of the ladder directly, rather than starting with opioid analgesics exert their analgesic effects via these receptors,
the first two.11 whether they are high- or low-affinity µ-agonists, or whether
they are µ-receptor dualists. Naloxone is an opioid-receptor
As illustrated in Figure 1, opioids play an important role in the
antagonist.1-4
management of, not only acute and chronic pain, but also in
the management of moderate to severe pain.12 However, certain Also note that the opioid analgesics, in contrast to the nonsteroidal
barriers limit the effective use of opioids in the management of anti-inflammatory drugs (or NSAIDs), cannot be used in the
pain, as explained below13: management of pyrexia (fever) or inflammation. The non-opioid
• Concerns about the use of opioids from healthcare professionals, analgesics act within peripheral tissues, where they facilitate
family members and patients; such concerns may be related to the inhibition of pain impulse formation. The prostaglandins are
the side-effect profile and perceived risk of dependence when important mediators of somatic pain sensations, or so-called
using the opioids. dermal, subcutaneous and musculoskeletal pain.1

Severe pain
Persistent or
worsening pain

Moderate pain

Strong opioid analgesics:

Mild to moderate pain Morphine, hydromorphone, oxycodone,
Weak opioid analgesics: buprenorphine or tapentadol*;
Codeine, dextropropoxyphene, tramadol With / without a non-opioid, such as
or buprenorphine; aspirin, paracetamol or ibuprofen;
Non-opioid analgesics: With / without a non-opioid, such as With / without an adjuvant*
Aspirin, paracetamol or ibuprofen; aspirin, paracetamol or ibuprofen;
With / without an adjuvant* With / without an adjuvant*

[*Examples of adjuvants include corticosteroids, antidepressants, hypnotics and anticonvulsants/antiepileptic agents.]

Figure 1: The World Health Organization’s three-step analgesic ladder (adapted and examples added)11

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In patients with severe pain, morphine is typically regarded as the 80 mg in packs of 28 tablets. The tablets should be taken at
gold standard for strong opioids. However, careful consideration 12-hourly intervals. After administration, the onset of analgesia
needs to be given to the following agents as well: may occur within 37 minutes and it provides an analgesic effect
• Oxycodone for up to 12 hours.16 Prolonged-release tablets should not be
broken, crushed or chewed, as this may result in a toxic dosage
• Hydromorphone
of the drug being delivered. Patient counselling should include
• Buprenorphine dietary advice (intake with a high-fat meal may increase peak
• Tapentadol (currently not marketed in South Africa) plasma levels) and information on the fact that the matrix
core can be passed in the stools, since it does not dissolve
Each of these drugs will be looked at in more detail.
completely.16,17 In addition, patients need to be informed of the
Oxycodone abuse potential of any strong opioid agonist, as well as the risk
of theft of their pain medication.
Oxycodone is classified as a mild-to-moderate, partial agonist at
the mu- (µ) and kappa- (κ) opioid receptors, with strong analgesic • General side-effects are similar to the ones associated with
properties.4,14 It is a semisynthetic agent, derived from the other strong opioids, including nausea, vomiting, sedation,
opium alkaloid, thebaine.4,14 It has been used for many years, in constipation, dizziness and pruritus.16,17 It may cause respiratory
combination with paracetamol, for chronic pain, but more recent depression and these effects should be monitored. In patients
clinical trial data revealed that it might be more efficacious and suffering from renal impairment (with a creatinine clearance
safe when used by itself, in a controlled-release, or an immediate- of ≤ 60 ml/min), the initial dosage of the prolonged-release
release formulation.4,14 In addition, it has been shown that formulation should be reduced and adjusted according to the
conversion to oxymorphone is not required for its bioactivity; patient’s clinical status.16,17 In patients with hepatic impairment,
meaning that the drug has a high oral bioavailability and is twice the prolonged release formulations should be initiated at 33–
as potent as morphine.14 50% of the dosage that would otherwise be recommended.16,17

Both immediate-release (IR) and prolonged-release (PR) The release of oxycodone from Oxycontin® prolonged release
preparations are marketed in South Africa.15,16 tablets is biphasic with an initial, relatively fast release providing
an early onset of analgesia, followed by a more controlled release,
• Immediate-release preparations (Oxynorm® capsules): The
which ensures the 12-hour duration of action.
conventional preparations of oxycodone can be used orally for
the management of moderate to severe pain in conditions such Hydromorphone
as bursitis, dislocations, etc. It may also be used for postoperative
Hydromorphone is a hydrogenated, semi-synthetic, potent mu-
pain management, post-extraction and postpartum pain.16
(µ) receptor agonist with a weak affinity for kappa- (κ)receptors. It
The approved indication for Oxynorm® is as follows: indicated
is used to treat moderate to severe pain.4,18,19 It is five to ten times
for the treatment of moderate to severe pain in patients with
more potent than morphine and due to alterations in its chemical
cancer, and postoperative pain, once gastrointestinal function
structure (a keto-group instead of a hydroxyl group at position 6,
has returned. It is also indicated for the treatment of severe pain
when compared to morphine), it has enhanced distribution into
requiring the use of a strong opioid analgesic. This product is
the CNS.20
available in 5, 10 and 20 mg strengths, in packs of 28 capsules.15
The capsules should be taken at 4–6 hourly intervals. After A controlled-release formulation of oral hydromorphone is the
oral administration, an analgesic effect may occur within only one that is currently approved for the South African market
10–15 minutes, and may persist for 3–6 hours.16 (Jurnista®, 8 and 16 mg tablets), although powder and oral
• Prolonged-release preparations (Oxycontin® prolonged- solutions, injections, and rectal suppositories are available in the
release tablets): This product may be used orally for the relief USA.16 These formulations maintain consistent hydromorphone
of moderate to severe pain in situations where continuous plasma concentrations throughout the 24-hour dosing interval,
analgesia is needed, for instance in cancer and persistent, non- ensuring long-lasting analgesia. The hydromorphone is actively
malignant pain, or pain during rehabilitation.16 The approved released from the matrix system by the dosage form itself, with
indication for Oxycontin® is as follows: indicated for the minimal effects from food and alcohol (as it is not influenced by
treatment of moderate to severe pain in patients with cancer, gastric pH or motility).16,18,19
and postoperative pain, once gastrointestinal function has
Hydromorphone is well absorbed after oral intake, and when
returned. It is also indicated for the treatment of severe pain
compared to morphine it has a faster onset of action, but with a
requiring the use of a strong opioid analgesic. The prolonged
shorter duration of action. This can be advantageous in the short-
release tablets are not indicated for use in preoperative
term analgesia setting.20
analgesia, or for pain during the immediate (i.e. the first
24 hours) phase post-surgery, nor for mild, short-term or acute Hydromorphone has the same side-effect profile as other opiate
use. The preparation should also not be used on an “as-needed” agonists; however, nausea, vomiting, constipation and euphoria
basis.14,16,17 The available preparations include 5, 10, 20, 40 and may be less pronounced with hydromorphone, when compared

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to morphine.16,21 Safety and efficacy has not been established in The following important drug interactions have been identified
children, and in patients over the age of 65 years.16,22 with the use of buprenorphine16:

Buprenorphine • Non-selective MAO-inhibitors enhance the effects of

buprenorphine. This can result in anxiety, confusion and
Buprenorphine is a partial opioid receptor agonist (i.e. an agonist- respiratory depression. These two agents should, therefore, not
antagonist). It binds to the mu- (µ) receptors with great affinity, be used concomitantly, or by patients who took MAO-inhibitors
but has a low intrinsic activity. It also has an affinity for the kappa- in the prior 14 days.
(κ) receptors. The rate of dissociation from the µ-receptors is slow,
• Inhibitors of CYP450 3A4 result in higher plasma concentrations,
which results in an antagonistic effect to any other opioids that
e.g. macrolide antibiotics, HIV protease inhibitors and calcium
may be co-administered with buprenorphine.23,24 Buprenorphine
antagonists. There is also an efficacy reduction from increased
is a partial agonist, and when compared with full agonists, has a
hepatic clearance with concurrent use of CYP3A4 enzyme
lower liability for the induction of physical dependence.22,23
inducers, e.g. carbamazepine, phenytoin and phenobarbitone.
When taken orally, buprenorphine undergoes first-pass hepatic • CNS depressants and muscle relaxants: Caution must be taken
metabolism with N-dealkylation and glucoroconjugation in the when using drugs that suppress respiration and the CNS, e.g.
small intestine. It is oxidatively metabolised by CYP3A4 and by sedatives or hypnotics, general anaesthetics, other opioid
glucoroconjugation of the parent molecule and the dealkylated analgesics, phenothiazines, centrally-acting antiemetics,
metabolite (norbuprenorphine).22,23 Distribution is rapid and benzodiazepines and alcohol.
the half-life is two to five hours. The conjugated metabolites are
excreted, mostly in the faeces, via biliary excretion (80%), but also The most commonly experienced adverse effects are constipation,
in the urine.23 headaches, insomnia, asthenia, drowsiness, nausea and vomiting,
fainting and dizziness, orthostatic hypotension and sweating.
Due to its high potency, low molecular weight and lipophilicity, Pruritus or erythema at the application site of the transdermal
it is also suitable for transdermal administration.15 Each patches are rare.15,22-24
buprenorphine-base transdermal patch provides a steady delivery
of buprenorphine for up to seven days. Steady state is achieved Tapentadol
during the first application. After removal of the buprenorphine-
Tapentadol is not available in South Africa yet. The drug has a
base transdermal patch, the buprenorphine concentration will
novel, dual mechanism of action as a combined mu- (µ) opioid
decline; decreasing by approximately 50% in 12 hours (range
receptor (MOR) agonist, and as a noradrenaline-reuptake inhibitor
10–24 hours). The absorption does not vary significantly across
(NRI). The chemical structure of tapentadol is unlike that of other
the specified application sites. Mean exposure (i.e. the AUC) at
opioids, such as morphine, but resembles tramadol the most.
each of the application sites is within ± 11% of the mean exposure
The combination of µ-opioid receptor agonism and noradrenalin
for the four sites. Following buprenorphine-base transdermal
reuptake inhibition offers the following mechanisms in pain
patch application, buprenorphine diffuses from the patch
management25-27:
through the skin. Buprenorphine is approximately 96% bound to
plasma proteins. Buprenorphine metabolism in the skin, following • The µ-opioid receptor agonism of the afferent pain fibres
buprenorphine-base transdermal patch application, is negligible. inhibits the release of excitatory neurotransmitters and
Norbuprenorphine, is the only known active metabolite of reduces the upward transmission of pain signals. The effects
buprenorphine.4,15,22-24 on the brain include an inhibitory influence on the release of
neurotransmitters by the descending pain pathways, providing
In South Africa, three buprenorphine-containing products are further inhibition of pain.
currently being marketed, namely:
• The noradrenaline reuptake inhibition has an antinociceptive
• Sovenor® 5, 10 and 20 mcg/hour transdermal patches effect, via the descending pain pathways, through a reduction
• Subutex® 2 and 8 mg sublingual tablets in pain signals to the brain.
• Temgesic® 0,2 mg sublingual tablets, as well as a solution for
These two mechanisms act synergistically to provide an overall
parenteral injection, of 0.3 mg/ml.
state of analgesic pain relief.26 Current formulations available in the
The Sovenor® transdermal patches are indicated for the treatment United States include tablets and film-coated tablets in strengths
of chronic musculoskeletal pain of the joints and the lower back, of 50, 75 and 100 mg.16 Patients with mild to moderate renal
when that pain is of moderate to severe intensity and sufficient to impairment, and mild hepatic impairment do not require dosage
require an opioid to attain adequate levels of analgesia. There are adjustments.16,25 However, clinical studies have not been done in
three different strengths available, and the patches release 5 mcg, patients with severe renal or hepatic impairment and tapentadol
10 mcg and 20 mcg, respectively, of buprenorphine per hour over should therefore not be used in this patient population. Patients
a period of seven days. Therefore, they only need to be replaced with moderate hepatic impairment should use the drug with
once a week. The patches offer a convenient ultra-low dosage to caution and any required dosage adjustments should be made.16,25
start with. The drug is contra-indicated in the following settings16:

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• Concurrent or recent (within two weeks) use of a monoamine • There is a very real danger that the full µ-receptor agonists will
oxidase (MAO) inhibitor. cause dependency; the dualists generally do not cause this
• Substantial respiratory depression in a setting where it cannot problem.
be monitored or where there is no resuscitation equipment at • Pethidine (also known as meperidine) has a rapid onset of
hand. action, but its analgesic effects are limited to a few hours
• Acute or severe bronchial asthma, where the condition cannot in duration. It has a toxic metabolite that accumulates with
be monitored or where there is no resuscitation equipment repeated administration, which makes it poorly suited to
available. the management of chronic pain, but it is still suited to the
postoperative setting. It is the opioid drug of choice in obstetrics,
Tapentadol is metabolised by hepatic microsomal enzymes and, in ureter colic and biliary obstruction (its action on smooth muscle
particular, by cytochrome P-450 (CYP) isoenzymes 2C9, 2C19 and is less pronounced than that of the other opioid analgesics).
2D6. The only isoenzyme that was inhibited to a limited extent
• Other examples of opioid analgesics include methadone (high
in vitro, was CYP2D6, but the concentrations required are clinically
potency) and dextropropoxyphene (low potency). In addition,
irrelevant. Potential drug interactions may include the following
oxycodone and hydromorphone (both phenanthrenes) are two
drug groups16,27:
more examples of high-potency opioids that may be used in
• Monoamine oxidase inhibitors, as discussed in the text. cases of severe pain. Furthermore, methadone has the ability
• Serotonergic drugs causing serious to fatal serotonin syndrome, to act as an antagonist at NMDA-receptors and to block the
e.g. the triptans. reuptake carriers of the monoaminergic transmitters, and it is
• CNS depressants, e.g. sedatives, tranquilisers, alcohol, etc. long-acting.
• Morphine, and the other opioid analgesics to varying degrees,
Other precautions are similar to general opiate agonist
can elicit adverse effects such as respiratory depression, truncal
precautions.27 Side-effects may include nausea, dizziness,
rigidity, sedation, nausea and vomiting, urinary retention,
vomiting, somnolence, constipation, pruritus, dry mouth,
constipation, miosis, tolerance and dependence.
hyperhidrosis and fatigue.16,22 Gastrointestinal effects (nausea,
vomiting and constipation) have been reported, but tapentadol • Naloxone is a competitive antagonist at the opioid receptors
may have an ‘opioid-sparing’ effect with less opioid-related side- but has a shorter half-life than morphine has, for instance. It may
effects.16,26,27 be used in cases of morphine and other opioid overdosage.

In summary Conclusion
Four key drug examples have been discussed in the aforementioned The effective management of pain requires a multidisciplinary
section. However, a few over-all remarks are herewith summarised healthcare approach. The clear, step-wise escalation pathway, as
for the opioid analgesics in general1-4: recommended by the WHO in its analgesic ladder, provides strong
• The opioid analgesics act as either full agonists (of high or low guidelines in terms of the escalation to opioid-based analgesia
affinity) or partial agonists (dualists) at the opioid receptors. (in cases of moderate to severe pain and discomfort). Healthcare
Morphine is more water-soluble than codeine. It is a high-affinity professionals need to make appropriate recommendations and
agonist at µ-receptors and a very potent opioid. Codeine is not provide effective advocacy for the use of the more potent opioid
nearly as potent as morphine (it is a low-affinity agonist). The analgesics, whenever these should become appropriate and
µ-agonists also cause smooth muscle contraction, and therefore necessary. In addition, the use of adjuvant treatment options
produce a spastic paralysis of the small intestine, which leads should be considered during each one of the three steps in the pain
to constipation. At dosages that are lower than those required ladder, since the augmentation of pure analgesia will strengthen
for effective analgesia, codeine may be used as an antitussive the patient’s experience of symptomatic relief. Pharmacists need
(i.e. a cough suppressant) as well as an anti-diarrhoeal agent. to have a clear understanding of the various treatment options, as
Dihydrocodeine is a more potent analgesic than the latter. well as their indications, side-effects and contra-indications.
• Pethidine, dipipanone and fentanyl (as well as sufentanil,
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S Afr Pharm J 49 2018 Vol 85 No 1

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