opioids in pain medicine

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39Guide to Pain Management in Low-Resource Settings, edited by Andrea s Kopf and Nilesh B. Patel. IASP, Seattle, 2010. All rights reserved. Tis material may be used for educationaland training purposes with proper citation of the source. Not for sale or commercial use. No responsibility is assumed by IASP for any injury and/or damage to persons or propertyas a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of the rapid advances in themedical sciences, the publisher recommends that there should be independent verification of diagnoses and drug dosages. Te mention of specific pharmaceutical products and any

medical procedure does not imply endorsement or recommendation by the editors, authors, or IASP in favor of other medical products or procedures that are not covered in the text.

Guide to Pain Management in Low-Resource Settings

Michael Schfer

Chapter 7

Opioids in Pain Medicine

Classification of opioids

reatment of pain very quickly reaches its limits. Any-

one who has suffered from a severe injury, a renal or gall

bladder colic, a childbirth, a surgical intervention, or an

infiltrating cancer has had this terrible experience and

may have experienced the soothing feeling of gradual

pain relief, once an opioid has been administered. In

contrast to many other pain killers, opioids are still the

most potent analgesic drugs that are able to control se-

vere pain states. Tis quality of opioids was known dur-ing early history, and opium, the dried milky juice of the

poppy flower, Papaver somniferum, was harvested not

only for its euphoric effect but also for its very powerful

analgesic effect. Originally grown in different countries

of Arabia, the plant was introduced by traders to other

places such as India, China, and Europe at the begin-

ning of the 14th century.

At that time, the use of opium for the treatment

of pain had several limitations: it was an assortment

of at least 20 different opium alkaloids (i.e., substances

isolated from the plant), with very divergent modes of

action. Overdosing occurred quite often, with many

unwanted side effects including respiratory depres-

sion, and, because of irregular use, the euphoric effects

quickly resulted in addiction.

With the isolation of a single alkaloid, mor-

phine, from poppy flower juice by the German phar-

macist Friedrich Wilhelm Sertrner (1806) and the

introduction of the glass syringe by the French ortho-

pedic surgeon Charles Pravaz (1844), much easier han-

dling of this unique opioid substance became possible

with fewer side effects.

oday we distinguish naturally occurring opi-

oids such as morphine, codeine, and noscapine from

semisynthetic opioids such as hydromorphone, oxy-

codone, diacetylmorphine (heroin) and from fully syn-

thetic opioids such as nalbuphine, methadone, pentazo-

cine, fentanyl, alfentanil, sufentanil, and remifentanil.

All these substances are classified as opioids, includingthe endogenous opioid peptides such as endorphin, en-

kephalin, and dynorphin which are short peptides se-

creted from the central nervous system under moments

of severe pain or stress, or both.

Opioid receptors andmechanism of action

Opioids exert their effects through binding to opi-

oid receptors which are complex proteins embedded

within the cell membrane of neurons. Tese recep-

tors for opioids were first discovered within specif-

ic, pain related brain areas such as the thalamus, the

midbrain region, the spinal cord and the primary sen-

sory neurons. Accordingly, opioids produce potent

analgesia when given systemically (e.g., via oral, intra-

venous, subcutaneous, transcutaneous, or intramus-

cular routes), spinally (e.g., via intrathecal or epidural


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40 Michael Schfer

routes), and peripherally (e.g., via intra-articular or

topical routes).

oday, three different opioid receptors, the-, -, and -opioid receptor, are known. However, the

most relevant is the -opioid receptor, since almost all

clinically used opioids elicit their effects mainly through

its activation. Te three-dimensional structure of opioid

receptors within the cell membrane forms a pocket at

which opioids bind and subsequently activate intracellu-

lar signaling events that lead to a reduction in the excit-

ability of neurons and, thus, pain inhibition. According

to their ability to initiate such events, opioids are dis-

tinguished as full opioid agonists (e.g., fentanyl, sufen-tanil) that are highly potent and require little receptor

occupancy for maximal response, partial opioid agonists

(e.g., buprenorphine) that require greater receptor oc-

cupancy even for a low response, and antagonists (e.g.,

naloxone, naltrexone) that do not elicit any response.

Mixed agonists/antagonists (e.g., pentazocine, nalbu-

phine, butorphanol) combine two actions: they bind to

the -receptor as agonists and to the -receptor as an-

tagonists.

Opioid-related side effects

Te first time opioids are taken, patients frequently

report acute side effects such as sedation, dizziness,

nausea, and vomiting. However, after a few days these

symptoms subside and do not further interfere with the

regular use of opioids. Patients should be slowly titrated

to the most effective opioid dose to reduce the severity

of the side effects. In addition, symptomatic treatments

such as antiemetics help to overcome the immediate

unpleasantness. Also, respiratory depression may be a

problem at the beginning, particularly when large doses

are given without adequate assessment of pain intensity.Dose titration and regular assessments of pain intensity

and breathing rate are recommended. During prolonged

and regular opioid application, respiratory depression is

usually not a problem. Cognitive impairment is an im-

portant issue at the beginning, particularly while driving

a car or operating dangerous machinery such as power

saws. However, patients on regular opioid treatment

usually do not have these problems, but all patients have

to be informed about the occurrence and possible treat-

ment of these side effects to prevent arbitrary discon-tinuation of medication. Constipation is a typical opioid

side effect that does not subside, but persists over the

entire course of treatment. It can lead to serious clinical

problems such as ileus, and should be regularly treated

with laxatives or oral opioid antagonists (see below).

Sedation

Opioid-induced reduction of central nervous system

activity ranges from light sedation to a deep coma de-

pending on the opioid used, the dose, route of applica-

tion, and duration of medication. In clinically relevantdoses, opioids do not have a pure narcotic effect, but

they also lead to a considerable reduction in the maxi-

mal alveolar concentration (MAC) of volatile anesthet-

ics used to induce unconsciousness during surgical pro-

cedures.

Muscle rigidity

Depending on the speed of application and dose, opi-

oids can cause muscle rigidity particularly in the trunk,

able 1List of different opioids that activate opioid receptors within the central nervous system

Opioid Alkaloids Semisynthetic Opioids Synthetic Opioids Opioid Peptides

Morphine

Codeine

Tebaine

Noscapine

Papaverine

Hydromorphone

Oxycodone

Diacetylmorphine (heroin)

Etorphine

Naloxone (antagonist)

Naltrexone (antagonist)

Nalbuphine

Levorphanol

Butorphanol

Pentazocine

Methadone

ramadol

Meperidine

Fentanyl

Alfentanil

Sufentanil

Remifentanil

Endorphin

Enkephalin

Dynorphin


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Opioids in Pain Medicine 41

abdomen, and larynx. Tis problem is first recognized

by the impairment of adequate ventilation followed by

hypoxia and hypercarbia. Te mechanism is not well

understood. Life-threatening diffi culty in assisted venti-

lation can be treated with muscle relaxants (e.g., succi-

nylcholine 50100 mg i.v., i.m.).

Respiratory depression

Respiratory depression is a common phenomenon

of all -opioid agonists in clinical use. Tese drugs

reduce the breathing rate, delay exhalation, and pro-

mote an irregular breathing rhythm. Opioids reduce

the responsiveness to increasing CO2 by elevating

the end-tidal pCO2 threshold and attenuating the hy-

poxic ventilation response. Te fundamental drive

for respiration is located in respiratory centers of the

brainstem that consist of different groups of neuronal

networks with a high density of -opioid receptors.

Life-threatening respiratory arrest can be reversed bytitration with the i.v. opioid antagonist naloxone (e.g.,

0.40.81.2 mg).

Antitussive effects

In addition to respiratory depression, opioids suppress

the coughing reflex, which is therapeutically produced

by antitussive drugs like codeine, noscapine, and dex-

tromethorphan (e.g., codeine 51030 mg orally). Te

main antitussive effect of opioids is regulated by opioid

receptors within the medulla.

Gastrointestinal effects

Opioid side effects on the gastrointestinal system are

well known. In general, opioids evoke nausea and

vomiting , reduce gastrointestinal motility, increase

circular contractions, decrease gastrointestinal mu-

cus secretion, and increase fluid absorption, which

eventually results in constipation. In addition, they

cause smooth muscle spasms of the gallbladder, bili-

ary tract, and urinary bladder, resulting in increased

pressure and bile retention or urinary retention. Tesegastrointestinal effects of opioids are mainly due to

the involvement of peripheral opioid receptors in the

mesenteric and submucous plexus, and are due to a

lesser extent to central opioid receptors. Terefore, ti-

tration with methylnaltrexone (100150300 mg oral-

ly), which does not penetrate into the central nervous

system, successfully attenuates opioid-induced consti-

pation. More common practice, however, is the coad-

ministration of laxatives such as lactulose (3 10 mg

to 3 40 mg/day orally), which is mandatory during

chronic opioid use.

Pruritus

Opioid-induced pruritus (itch) commonly occurs fol-

lowing systemic administration and even more com-

monly following intrathecal/epidural opioid adminis-

tration. Although pruritus may be due to a generalizedhistamine release following the application of morphine,

it is also evoked by fentanyl, a poor histamine liberator.

Te main mechanism is thought to be centrally medi-

ated in that inhibition of pain may unmask underlying

activity of pruritoreceptive neurons. Opioid-induced

pruritus can be successfully attenuated by naltrexone (6

mg orally) or with less impact on the analgesic effect by

mixed agonists such as nalbuphine (e.g., 4 mg i.v.).

Routes of opioid administrationOral

Te majority of opioids are easily absorbed from the

gastrointestinal tract with an oral bioavailability of 35%

(e.g., morphine) to 80% (e.g., oxycodone) entering the

circulation. However, they undergo to a high degree

(4080%) immediate first-pass metabolism in the liver,

where glucuronic acid binding makes the drug inactive

and ready for renal excretion. Exceptions are metabo-

lites of morphine, e.g., morphine-6-glucuronide, which

is itself analgesic, or morphine-3-glucuronide, which

is neurotoxic and can accumulate during renal impair-

ment as well as cause serious side effects such as re-

spiratory depression or neurotoxicity. Oral opioids are

commonly available in two galenic preparations, an

immediate-release formula (onset: within 30 min, du-

ration: 46 hours) and an extended-release formula

(onset: 3060 min, duration: 812 hours). Tere is pre-

liminary evidence for ethnic differences, e.g., between

Caucasians and Africans, with regard to the hepatic me-

tabolism of opioids, i.e., opioids exert a longer durationof action in Africans. Tis may be due in part to specific

genetic subtypes of the hepatic enzyme cytochrome

P-450, and in part due to the individual patients lifestyle

and habits.

Intravenous/intramuscular/subcutaneous

Tese different forms of parenteral opioid application

follow the same goals: a convenient and reliable way of

application, a fast onset of analgesic effect, and bypass


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42 Michael Schfer

of hepatic metabolism. While intravenous application

gives immediate feedback about the analgesic effect, in-

tramuscular and subcutaneous routes of administration

have some delay (about 1520 min) and should be given

on a fixed schedule to avoid large fluctuations in plasma

concentrations. Te faster rise in opioid plasma con-

centration with parenteral versus enteral applications

enables better and more direct control of opioid effects;however, it increases the risk of a sudden overdose with

sedation, respiratory depression, hypotension, and car-

diac arrest. After parenteral administration, a first phase

of opioid distribution within the central nervous system,

but also in other tissues such as fat and muscles, is fol-

lowed by a second, slower phase of redistribution from

fat and muscles into the circulation with the possibility

of the re-occurrence of some opioid effects. Tis phe-

nomenon is particularly important following repeated

administration.

Sublingual/nasal

Only highly lipophilic substances such as fentanyl and

buprenorphine can be administered by these routes,

because they easily penetrate the mucosa and are ab-

sorbed by the circulation. ime of onset of analgesia is

fast with fentanyl (0.050.3 mg; 5 min) but slower with

buprenorphine (0.20.4 mg; 3060 min). However, the

duration of analgesia is much longer with buprenor-

phine (68 hours) than with fentanyl (1545 min). Sim-

ilar to the other parenteral applications, there is no he-patic first-pass metabolism.

Intrathecal/epidural

Opioids administered intrathecally or epidurally pen-

etrate into central nervous system structures depend-

ing on their chemical properties: less ionized, i.e. more

lipophilic, compounds such as sufentanil, fentanyl, or

alfentanil penetrate much (800 times) more easily than

more ionized, i.e. hydrophilic, compounds such as mor-

phine. While the lipophilic opioids are quickly taken up,

not only by the neuronal tissue, but also by epidural fatand vessels, a substantial amount of morphine remains

within the cerebrospinal fluid for a prolonged period

of time (up to 1224 hours) and is transported via its

rostral flow to the respiratory centers of the midbrain,

leading to delayed respiratory depression. Te effects of

opioids within the central nervous system are terminat-

ed by their redistribution into the circulation and not by

their metabolism, which is negligible. Doses for epidu-

ral morphine, for example, are a bolus dose of 1.03.0

mg, and a 24-h dose of 3.010 mg; and for intrathecal

morphine a bolus dose of 0.10.3 mg, and a 24-h dose

of 0.31.05.0 mg.

Morphine

Morphine, a strong -opioid agonist that is recommend-

ed in step 3 of the WHO ladder, is commonly used as

a reference for all other opioids. It can be applied by allroutes of administration. Morphines active metabolites

morphine-6-glucuronide and morphine-3-glucuronide

can increase side effects such as respiratory depression

and neurotoxicity (excitation syndrome: hyperalgesia,

myoclonia, epilepsia), particularly when accumulation

occurs due to impairment of renal function. Its main in-

dications of use are for postoperative and chronic malig-

nant pain; however, it is also used for other severe pain

conditions (e.g., colic pain, angina pectoris). In acute

pain states, morphine can be quickly titrated to optimal

pain relief by the parenteral route (e.g., i.v. boluses of2.55 mg morphine), upon which the morphine plasma

concentration should be kept constant by regular timed

intervals of subsequent administrations (e.g., 612 mg

i.v. morphine/h). In chronic pain conditions, daily mor-

phine doses should be given in an extended-release

formula, and breakthrough pain is best treated by ad-

ministration of a fifth of the daily morphine dose in an

immediate-release formula. Regular monitoring of pain

intensity and morphine consumption is desirable.

able 2Equianalgesic doses of different routes of

administrations of opioids

Drug Dose (mg)Conversion

Factor

Morphine, oral 30 1

Morphine, i.v., i.m., s.c. 10 0.3

Morphine, epidural 3 0.1

Morphine, intrathecal 0.3 0.01

Oxycodone, oral 20 1.5

Hydromorphone, oral 8 3.75

Methadone, oral 10 0.3

ramadol, oral 150 0.2

ramadol, i.v. 100 0.1

Meperidine, i.v. 75 0.13

Fentanyl, i.v. 0.1 100

Sufentanil, i.v. 0.01 1000

Buprenorphine, s.l. 0.3 100


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Oxycodone

Oxycodone is a strong oral -opioid agonist belonging

to step 3 of the WHO ladder, with 1.5 times the anal-

gesic potency of morphine. Oxycodone has a high oral

bioavailability of 6080%. It is metabolized in multiple

steps to different metabolites, of which oxymorphone

is the most active and 8 times more potent than mor-phine. Oxycodone has a similar therapeutic profile to

morphine; however, it is only available as an oral ex-

tended-release formulation (1080 mg tablets). Since

these tablets have a relatively high dose, they can be pul-

verized and made into an aqueous solution, which has

been misused for its euphoric effects by addicts.

Hydromorphone

Hydromorphone is a -opioid agonist belonging to step

3 of the WHO ladder (strong opioids) with 45 timesthe analgesic potency of morphine. After oral applica-

tion (single dose 4 mg), the onset of analgesia occurs af-

ter 30 min and lasts up to 46 hours. Because of its high

water solubility, it is available as both an oral and par-

enteral formulation (2 mg/1 amp.) that can be adminis-

tered i.v., i.m., or s.c. Hydromorphone is extensively me-

tabolized in the liver, with metabolism of approximately

60% of the oral dose. Te metabolite hydromorphone-

3-glucuronide can cause neurotoxic effects (excitation

syndrome: hyperalgesia, myoclonus, epilepsy), similar tomorphine-3-glucuronide.

Methadone

Methadone is a -opioid receptor agonist with 0.3

times the analgesic potency of morphine. In addition

to its opioid receptor activity, it is also an antagonist

of theN-methyl-D-aspartate (NMDA) receptor, which

might be advantageous in chronic pain states such as

neuropathic pain in which the NMDA receptor seems

to be responsible for the persistent pain hypersensi-tivity. Methadone is a lipophilic drug with good CNS

penetrability and high bioavailability (4080%). It ex-

ists as an oral (540 mg tablets) and parenteral for-

mulation (levomethadone: 5 mg/mL). Methadone is

metabolized with no active metabolites by multiple

different enzymes of the liver in a highly variable

manner, which explains its broad variation of half-life

(up to 150 h) and makes regular dosing quite diffi cult

for patients. In general, pain relief is better obtained

with methadone doses that are 10% of the calculated

equianalgesic doses of conventional opioids. Excretion

occurs almost entirely in the feces, which makes it a

good candidate for patients with renal failure. Metha-

done has a much lower propensity for euphoric effects

and is therefore used in maintenance programs for

drug addicts. In addition, there is incomplete cross-

tolerance to other opioids. Unfortunately, methadonehas the potential to initiate orsades de Pointes, a po-

tentially fatal arrhythmia caused by a lengthening of

the Q interval in the ECG.

Tramadol

ramadol, a weak opioid, belongs to step 2 of the

WHO ladder. ramadol itself binds to norepinephrine

and serotonin reuptake inhibitors, which increases lo-

cal concentrations of norepinephrine and serotonin,

leading to subsequent pain inhibition. In addition, one

of its metabolites (M1) binds to the -opioid receptor,

which elicits additional analgesia. ramadol has a high

bioavailability of 60% and 0.2 times the analgesic po-

tency of morphine. Since the opioid component is de-

pendent on hepatic metabolism to the M1 compound,

genetic variations may differentiate poor from exten-

sive metabolizers, and hence the respective differences

in analgesic effects. ramadol exists as an oral (50

100150200 mg tablets) and parenteral formulation

(50100 mg). As with all opioids, hepatic and renalimpairment may lead to accumulation of the drug with

an increased risk of respiratory depression. Because of

potential interactions, tramadol should not be given

together with monoamine oxidase inhibitors, since the

combination may produce severe respiratory depres-

sion, hyperpyrexia, central nervous system excitation,

delirium, and seizures.

Meperidine

Meperidine, a weak -opioid agonist, belongs to step 2of the WHO ladder with 0.13 times the analgesic po-

tency of morphine and significant anticholinergic and

local anesthetic properties. Meperidine is most often

used postoperatively, since in addition to its analgesic

effects, it has anti-shivering properties. Meperidine ex-

ists as an oral (50 mg/mL solution) and parenteral for-

mulation (50100 mg/2 mL). It is metabolized in the

liver to normeperidine with a half-life of 1530 hours,

and has significant neurotoxic properties. Meperidine


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44 Michael Schfer

should not be given to patients being treated with

monoamine oxidase inhibitors (MAOI), since the

combination may produce severe respiratory depres-

sion, hyperpyrexia, central nervous system excitation,

delirium, and seizures.

Fentanyl

Fentanyl, a strong -opioid agonist, belongs to step 3 of

the WHO ladder with 80100 times the analgesic po-

tency of morphine. Fentanyl mainly exists as a paren-

teral formulation (0.1 mg/2 mL); however, sublingual

application is sometimes used. A transdermal applica-

tion system is widely used in industrial countries, but

because of its costs and the delayed delivery system

with additional risks (delayed respiratory depression), it

may only be of use in rare cases. Fentanyl is metabo-

lized in the liver to inactive metabolites. Te rapid on-

set, high potency, and short duration of fentanyl is an

advantage in the titration and controllability of periop-

erative pain. However, incorrect use may lead to large

fluctuations in plasma concentration and increase the

risk of psychological dependence and addiction. Impor-

tantly, repeated administration of fentanyl may lead to

drug accumulation due to redistribution from fat and

muscle tissue into the circulation with increased risk of

respiratory depression.

SufentanilSufentanil, a very strong -opioid agonist, with 800

1000 times the analgesic potency of morphine, is ex-

clusively available as a parenteral formulation (0.25

mg/5 mL) and can be given i.v. (10100 g boluses)

as well as epidurally (initially: 510 g, repeated bo-

lus: 0.51 g). Because of its very high potency, suf-

entanil is mainly used intraoperatively. In comparison

to fentanyl, it is much less prone to drug accumula-

tion, because of its low tissue distribution, low pro-

tein binding, and high hepatic metabolization rate toinactive metabolites.

Buprenorphine

Buprenorphine belongs to the mixed agonist/antago-

nist opioids binding to - and k-opioid receptors. It

usually has a slow onset (4590 min), a delayed maxi-

mal effect (3 hours), and a long duration of action

(810 hours). Buprenorphine is available as sublingual

(s.l.) (0.20.4 mg capsules) and parenteral (0.3 mg/

mL) formulations. Its metabolites are inactive and are

mainly excreted via the biliary duct. Oral bioavailabil-

ity is 2030% and sublingual bioavailability is 3060%.

For acute pain, 0.20.4 mg s.l. buprenorphine or 0.15

mg i.v. is applied every 46 hours. Because of its very

stable and long duration of action, buprenorphine is

used for substitution therapy for drug addicts (432mg/daily). Similar to fentanyl, there is a transdermal

application system. Buprenorphines respiratory de-

pressant effects are reversed only by relatively large

and repeated doses of naloxone (24 mg).

Naloxone/naltrexone

Both substances are classical opioid receptor antago-

nists with a preference for -opioid receptors. Naloxone

is available only as a parenteral formulation (0.4 mg/1

mL), and it has a fast onset (within 5 min) and a short

duration (306090 min) of action. It is commonly used

preoperatively to treat opioid overdosing and needs to

be titrated and administered repeatedly under constant

monitoring. Naltrexone exists only as an oral formula-

tion (50 mg/tablet) with a delayed onset (within 60 min)

and a long duration (1224 h) of action. Naltrexone is

mainly used for maintenance treatment for alcohol and

drug dependence. Both substances can precipitate acute

life-threatening withdrawal symptoms when improperly

used, e.g., hyperexcitability, delirium, hallucinations, hy-peralgesia, hypertension, tachycardia, arrhythmia, and

increased sweating.

Pearls of wisdom

Although they have been available for almost

200 years, opioids still remain the mainstay of

pain management. While opioids are effective

in most postoperative and cancer patients, and

in some patients with neuropathic pain, most

other noncancer pain is hardly responsive toopioid medication.

While opioids are regarded with a lot of preju-

dice because of their side effects and abuse po-

tential, clinical practice and research have dem-

onstrated in the last few decades that opioid

medication for short- and long-term treatment

can be accomplished safely. Tere is no evidence

about a differential indication of the opioids

available. Consequently, availability, costs, and


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personal experience should be the guiding prin-

ciples when choosing an opioid.

Because there isas opposed to most drugs

used in medicineno organ toxicity, even at

high doses and with long-term treatment, and

because some important side effects diminish

over time and other potential harmful side ef-

fects may be avoided with correct use, it maybe that opioids will remain the mainstay of pain

management for most of our patients for some

time to come.

References

[1] Kaszor A, Matosiuk D. Non-peptide opioid receptor ligandsrecentadvances. Part I: Agonists. Curr Med Chem 2002;9:1567.

[2] Kurz A, Sessler DI. Opioid-induced bowel dysfunction. Drugs2003;63:64971.

[3] Massotte D, Kieffer BL. A molecular basis for opiate action. Essays Bio-chem 1998;33:6577.

[4] rescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. PainPhysician 2008;11:S13353.

[5] Pergolizzi J, Bger RH, Budd K, Dahan A, Erdine S, Hans G, Kress HG,Langford R, Likar R, Raffa RB, Sacerdote P. Opioids and the manage-ment of chronic severe pain in the elderly: consensus statement of anInternational Expert Panel with focus on the six clinically most oftenused World Health Organization Step III opioids (buprenorphine, fen-tanyl, hydromorphone, methadone, morphine, oxycodone). Pain Pract2008;8:287313.


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