Guide to Pain Management in Low-Resource Settings

Are there options to block calcium channels 
more eff ectively?
Neuronal cells have specifi c calcium channels (N-type 
calcium channels) that play a role in the communication 
between cells. Th
  e release of glutamate in nociception 
from the fi rst neuron for the activation of the second 
Table 1
Physicochemical and pharmacological data of acidic, nonselective COX inhibitors
Pharmacokinetic/Chemical 
Subclass
PK
A
Binding 
to Plasma 
Protein
Oral 
Bioavailability
t
max
t
50
Single Dose (Max. Daily 
Dose) for Adults
Short Elimination Half-Life
Aspirin* (acetylsalicylic acid)
3.5 (3.0)
50–70% 
(~80%)
50%, dose depen-
dent (1–5 h, dose 
dependent)
15 min 
(15–60 
min)
15 min
0.05–1 g (6 g) (not in use)
Ibuprofen
4.4
99%
100%
0.5–2 h
2 h
200–800 mg (2.4 g)
Flurbiprofen
4.2
>99%
~ 90%
1.5–3 h
2.5–4 (8) h
50–100 mg (200 mg)
Ketoprofen
5.3
99%
90%
1–2 h
2–4 h
25–100 mg (200 mg)
Diclofenac
3.9
99.7%
50%, dose depen-
dent
1–12 h, 
very vari-
able
1–2 h
25–75 mg (150 mg)
Long Elimination Half-Life
Naproxen
4.2
99%
90–100%
2–4 h
12–15 h
250–500 mg (1.25 g)
6–Methoxy-2–naphthyl-
acetic acid (active metabo-
lite of nabumetone)
4.2
99%
20–50%
3–6 h
20–24 h
0.5–1 g (1.5 g)
Piroxicam
5.9
99%
100%
3–5 h
14–160 
h
20–40 mg; initial dose: 
40 mg
Meloxicam
4.08
99.5%
89%
7–8 h
20 h
7.5–15 mg
* Aspirin releases salicylic acid (SA) before, during, and after absorption. Values in brackets refer to the active (weak) COX-1/COX-2 
inhibitor SA.

36
Kay Brune
neuron is also regulated by N-type calcium channels. 
Th
 e blockade of these channels blocks the infl ow  of 
calcium into glutamate cells, thus reducing glutamate 
release and activation of NMDA receptors. However, 
as these N-type channels are present in most neuronal 
cells, a general blockade would be incompatible with 
life. But recently ziconotide, a toxin from a sea snail, has 
been found to block these channels when administered 
directly into the spinal column, with tolerable side ef-
fects. Unfortunately, intrathecal administration of drugs 
is quite a sophisticated and expensive option for pain 
control, and presently it is done only at a few highly spe-
cialized pain centers for exceptional cases.
What other—more practical—options are 
available, when antiepileptic drugs fail to help?
Another option for treating pain in the clinical setting 
is the use of ketamine, which blocks use-dependent so-
dium channels of the glutamate NMDA receptor. Such 
receptors are not limited to the pain pathway, but are 
ubiquitously involved in neuronal communication. 
Consequently, the blockade of this sodium channel can-
not be limited to pain pathways, but a certain degree of 
selectivity is achieved by the use dependence. In other 
words, painful stimuli lead to a higher probability of 
opening of this channel, which can be accessed only in 
the open position by ketamine, which can then block it. 
Still, the relatively low specifi city of ketamine’s action 
causes many unwanted drug eff ects, ranging from “bad 
trips” (dysphoria) to lack of coherent thinking and at-
tention. Consequently, the use of ketamine is restricted 
to the clinical setting, in particular analgesic sedation. 
Nevertheless, low-dose ketamine (<0.2 mg/kg/h S-
ketamine or <0.4 mg/kg/h ketamine) maybe helpful as 
a “rescue medication” in uncontrolled pain, e.g., due to 
nerve plexus infi ltration in cancer. Unfortunately, as oral 
bioavailability is unpredictable, only the intravenous 
route can be used.
Pearls of wisdom
• Th
  e drugs discussed in this chapter allow for suc-
cessful treatment of most pain conditions, but 
not all.
•  It should be kept in mind that the most impor-
tant prototypes of the nonopioid analgesics are 
the COX inhibitors, which comprise the most 
widely used drugs worldwide because they are 
also given against fever, infl ammation, and many 
states of discomfort, including migraine. Due to 
their mode of action, their eff ect plateaus. In oth-
er words, the normalization of hyperalgesia ends 
when prostaglandin E
2
 production is completely 
suppressed. Increasing the dose will not increase 
the eff ect any further.
•  Constant inhibition of COXs in the vascular wall 
(selectively or nonselectively) leads to a constant 
blockade of the production of the vasoprotective 
factor prostacyclin (PGI
2
). Th
  is appears to be the 
main reason for the increased incidence of car-
diovascular events (heart attack, stroke, athero-
sclerosis), seen with the use of COX inhibitors, 
including acetaminophen (paracetamol).
Table 2
Physicochemical and pharmacological data of nonselective COX-2 inhibitors
Pharmacokinetic/ 
Chemical Subclass
COX-1/
COX-2 
Ratio
Binding 
to Plasma 
Protein
VD
Oral Bio-
availability
t
max
t
50
Primary Metabolism 
(Cytochrome 
P-450 Enzymes)
Single Dose (Max. 
Daily Dose) for 
Adults
Acetaminophen 
(paracetamol)
~ 20%
~70 L
~ 90%
1 h
1–3 h
Oxidation (direct sul-
fation)
1 g (4 g)
Celecoxib
30
91%
400 L
20–60%
2–4 h
6–12 h
Oxidation (CYP2C9, 
CYP3A4)
100–200 mg (400 
mg) for osteoarthro-
sis and rheumatoid 
arthritis
Etoricoxib
344
92%
120 L
100%
1 h
20–26 h
Oxidation to 6’-hydroxy-
methyl-etoricoxib (major 
role: CYP3A4; ancillary 
role: CYP2C9, CYP2D6, 
CYP1A2)
60 mg (60 mg) for 
osteoarthrosis, 90 
mg (90 mg) for 
rheumatoid arthri-
tis, 120 mg (120 
mg for acute gouty 
arthritis

Pharmacology of Analgesics (Excluding Opioids)
37
•  Still, comparing the unwanted drug side effects 
of all analgesic compounds, including opiates, 
one would come to the conclusion that they 
all have their problems. They should be used 
in serious pain, but not as a means to decrease 
daily discomfort; only then is their use mean-
ingful and justifiable.
Table 3
Major side eff ects, drug interactions, and contradictions of COX inhibitors
Drug
Adverse Drug 
Reactions*
Drug Interactions
Contradictions (Absolute and Relative)
Nonselective, Acidic Drugs
Aspirin
Inhibition of platelet 
aggregation for days, 
aspirin-induced asthma, 
ulcerations, bleeds
Vitamin K antagonists
Hypersensitivity to the active substance or to any of the 
excipients, impaired blood coagulation, pregnancy and all 
contradictions listed below
Diclofenac
Ibuprofen
Indomethacin
Ketoprofen
Ketorolac
Naproxen
Meloxicam
GI ulcerations, dys-
pepsia, increased BP, 
water retention, allergic 
(asthmatic) reactions, 
vertigo, tinnitus
ACE inhibitors, glucocor-
ticoids, diuretics, lithium, 
SSRIs, ibuprofen: reduction 
of low-dose aspirin cardio-
protection
Asthma, acute rhinitis, nasal polyps, angioedema, urti-
caria or other allergic-type reactions after taking ASA or 
NSAIDs; active peptic ulceration or GI bleeds; infl am-
matory bowel disease; established ischemic heart disease, 
peripheral arterial disease and/or cerebrovascular disease; 
renal failure
Selective (Preferential) COX-2 Inhibitors
Acetaminophen 
(paracetamol)
Liver damage
Not prominent
Liver damage, alcohol abuse
Celecoxib
Allergic reactions (sul-
fonamide)
Blocks CYP2D6; interac-
tions with SSRIs and beta-
blockers
Existing pronounced atherosclerosis, renal failure
Etoricoxib
Water retention, in-
creased blood pressure
Reduces estrogen metabo-
lism
As with celecoxib, plus insuffi
  cient control of blood pres-
sure; cardiac insuffi
  ciency
* More pronounced in highly potent and/or slowly eliminated drugs (all except ibuprofen)
Table 4
Pharmacokinetic data on non-COX, nonopioid analgesics
Type (Drug)
t
50
Common Dosing
Adverse Reactions
Antiepileptics
Carbamazepine
~2 days
~0.5 g b.i.d.
1
Diplopia, ataxia (aplastic anemia)
Gabapentin
~6 hours
~1 g b.i.d.
Somnolence, dizziness, ataxia, headache, tremor
Pregabalin
~5 hours
~200 mg t.i.d.
Blockers of NMDA-receptor Na
+
-channels
Ketamine (race-
mic)
Fast,
2
 ~50 mg/d
0.5 mg/kg/h
Hypersalivation, hypertension, tachycardia, bad dreams
S
+
-Ketamine
As racemic, comp. S
+
-
ketamine, twice as active
N-Type Ca-Channel Blockers
3
Ziconotide
Permanent intrathecal 
administration
CNS disturbances from nausea to coma depending on the dose 
and distribution of the toxin, granuloma-formation
1
 No hard evidence for analgesic eff ects aside of trigeminal neuralgia; no dose recommendations for neuropathic pain available.
2
 Ketamine is highly lipophilic and sequesters into fat tissue (t
50
, distribution ~ 20 min); continuous infusion requires attention (to avoid 
overdosing).
3
 Only in desperate patients if intrathecal administration is possible.

38
Kay Brune
[5]  Hinz B, Renner B, Brune K. Drug insight: cyclo-oxygenase-2 inhibi-
tors—a critical appraisal. Nat Clin Pract Rheumatol 2007;3:552–60.
[6]  Zeilhofer HU, Brune K. Analgesic strategies beyond the inhibition of 
cyclooxygenases. Trends Pharmacol Sci 2006;27:467–74.
[7] Croff ord LJ, Breyer MD, Strand CV, Rushitzka F, Brune K, Farkouh ME, 
and Simon LS. Cardiovascular eff ects of selective COX-2 inhibition: is 
there a class eff ect? Th
  e International COX-2 Study Group. J Rheumatol 
2006;33:1403–8.
[8]  Brune K, Hinz B. Th
  e discovery and development of antiinfl ammatory 
drugs. Arthritis Rheumatol 2004;50:2391–9.
[9]  Brune K, Hinz B. Selective cyclooxygenase-2 inhibitors: similarities and 
diff erences. Scandinavian Journal of Rheumatol 2004;33:1–6.
References
[1]  Brune K, Hinz B, Otterness I. Aspirin and acetaminophen: should they 
be available over the counter? Curr Rheumatol Rep 2009;11:36–40.
[2]  Hinz B, Brune K. Can drug removals involving cyclooxygenase-2 inhibi-
tors be avoided? A plea for human pharmacology. Trends Pharmacol 
Sci 2008;8:391–7.
[3]  Brune K, Katus HA, Moecks J, Spanuth E, Jaff e AS, Giannitsis E. N-
terminal pro-B-type natriuretic Peptide concentrations predict the risk 
of cardiovascular adverse events from antiinfl ammatory drugs: a pilot 
trial. Clin Chem 2008;54:1149–57.
[4]  Knabl J, Witschi R, Hösl K, Reinold H, Zeilhofer UB, Ahmadi S, Brock-
haus J, Sergejeva M, Hess A, Brune K, Fritschy JM, Rudolph U, Möhler 
H, Zeilhofer HU. Reversal of pathological pain through specifi c spinal 
GABA
A
 receptor subtypes. Nature 2008;451:330–4.

39
Guide to Pain Management in Low-Resource Settings, edited by Andreas Kopf and Nilesh B. Patel. IASP, Seattle, © 2010. All rights reserved. Th
  is material may be used for educational 
and 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 property 
as 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 the 
medical sciences, the publisher recommends that there should be independent verifi cation of diagnoses and drug dosages. Th
  e mention of specifi c 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 Schäfer
Chapter 7
Opioids in Pain Medicine
Classifi cation of opioids
Treatment of pain very quickly reaches its limits. Any-
one who has suff ered from a severe injury, a renal or gall 
bladder colic, a childbirth, a surgical intervention, or an 
infi ltrating 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. Th
  is quality of opioids was known dur-
ing early history, and opium, the dried milky juice of the 
poppy fl ower,  Papaver somniferum, was harvested not 
only for its euphoric eff ect but also for its very powerful 
analgesic eff ect. Originally grown in diff erent 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 diff erent opium alkaloids (i.e., substances 
isolated from the plant), with very divergent modes of 
action. Overdosing occurred quite often, with many 
unwanted side eff ects including respiratory depres-
sion, and, because of irregular use, the euphoric eff ects 
quickly resulted in addiction.
With the isolation of a single alkaloid, mor-
phine, from poppy fl ower juice by the German phar-
macist Friedrich Wilhelm Sertürner (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 eff ects.
Today 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 classifi ed as opioids, including 
the 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 and       
mechanism  of action
Opioids exert their eff ects through binding to opi-
oid receptors which are complex proteins embedded 
within the cell membrane of neurons. Th
 ese recep-
tors for opioids were fi rst 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 

40
Michael Schäfer
routes), and peripherally (e.g., via intra-articular or 
topical routes).
Today, three diff erent opioid receptors, the 
μ-, δ-, and κ-opioid receptor, are known. However, the 
most relevant is the μ-opioid receptor, since almost all 
clinically used opioids elicit their eff ects mainly through 
its activation. Th
  e 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 κ-receptor as agonists and to the μ-receptor as an-
tagonists.
Opioid-related side eff ects
Th
 e fi rst time opioids are taken, patients frequently 
report acute side eff ects 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 eff ective opioid dose to reduce the severity 
of the side eff ects. 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 eff ects to prevent arbitrary discon-
tinuation of medication. Constipation is a typical opioid 
side eff ect 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 relevant 
doses, opioids do not have a pure narcotic eff ect,  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, 
Table 1
List of diff erent opioids that activate opioid receptors within the central nervous system
Opioid Alkaloids
Semisynthetic Opioids
Synthetic Opioids
Opioid Peptides
Morphine
Codeine
Th
 ebaine
Noscapine
Papaverine
Hydromorphone
Oxycodone
Diacetylmorphine (heroin)
Etorphine
Naloxone (antagonist)
Naltrexone (antagonist)
Nalbuphine
Levorphanol
Butorphanol
Pentazocine
Methadone
Tramadol
Meperidine
Fentanyl
Alfentanil
Sufentanil
Remifentanil
Endorphin
Enkephalin
Dynorphin

Opioids in Pain Medicine
41
abdomen, and larynx. Th
  is problem is fi rst  recognized 
by the impairment of adequate ventilation followed by 
hypoxia and hypercarbia. Th
 e mechanism is not well 
understood. Life-threatening diffi
  culty in assisted venti-
lation can be treated with muscle relaxants (e.g., succi-
nylcholine 50–100 mg i.v., i.m.).
Respiratory depression
Respiratory depression is a common phenomenon 
of all μ-opioid agonists in clinical use. Th
 ese drugs 
reduce the breathing rate, delay exhalation, and pro-
mote an irregular breathing rhythm. Opioids reduce 
the responsiveness to increasing CO
2
 by elevating 
the end-tidal pCO
2
 threshold and attenuating the hy-
poxic ventilation response. Th
 e fundamental drive 
for respiration is located in respiratory centers of the 
brainstem that consist of diff erent groups of neuronal 
networks with a high density of μ-opioid receptors. 
Life-threatening respiratory arrest can be reversed by 
titration with the i.v. opioid antagonist naloxone (e.g., 
0.4–0.8–1.2 mg).
Antitussive eff ects
In addition to respiratory depression, opioids suppress 
the coughing refl ex, which is therapeutically produced 
by antitussive drugs like codeine, noscapine, and dex-
tromethorphan (e.g., codeine 5–10–30 mg orally). Th
 e 
main antitussive eff ect of opioids is regulated by opioid 
receptors within the medulla.
Gastrointestinal eff ects
Opioid side eff ects 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 fl uid 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. Th
 ese 
gastrointestinal eff ects 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. Th
 erefore, ti-
tration with methylnaltrexone (100–150–300 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 generalized 
histamine release following the application of morphine, 
it is also evoked by fentanyl, a poor histamine liberator. 
Th
  e 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 eff ect by 
mixed agonists such as nalbuphine (e.g., 4 mg i.v.).