Guide to Pain Management in Low-Resource Settings

What is breakthrough pain?
Th
  e WHO has issued guidelines for matching the po-
tency of analgesics with the intensity of pain. Th
 e three-
step approach was recommended in 1990 and revised in 
1996. Th
  e WHO guidelines do not specifi cally  address 
breakthrough pain.
Th
 e transitory exacerbation of pain is de-
scribed in the medical literature by a number of diff er-
ent terms, such as breakthrough pain, transient pain, 
exacerbation of pain, episodic pain, transitory pain, or 
pain fl ow. An Expert Working Group of the European 
Association for Palliative Care (EAPC) has suggested 
that the term “breakthrough pain” should be replaced 
by the terms “episodic pain” or “transient pain.”
 
How-
ever, the term “breakthrough pain” is still widely used 
in the medical literature; therefore, this term will be 
used in this chapter, too.
Breakthrough pain is usually abrupt, acute, 
and can be very intense. Th
  e characteristics of break-
through cancer pain vary from person to person, in-
cluding the onset, duration, frequency of each episode 
and possible causes.
Breakthrough pain could be described as 
short-term pain exacerbation which is experienced by 
a patient who has relatively stable and adequately con-
trolled baseline pain. But currently, there is no univer-
sally accepted defi nition of breakthrough pain. Th
 ere 
are diagnostic algorithm and assessment tools for 
breakthrough pain, although they are not used very 
often in clinical practice. Breakthrough pain should be 
assessed in a similar manner to background pain, with 
a pain history and physical examination.
Why should attention to 
breakthrough pain be increased?
Breakthrough pain is common in cancer patients, 
and also in patients with other types of pain. Unfor-
tunately, it is underdiagnosed and under-recognized 
by health care professionals. An IASP survey on can-
cer pain characteristics and syndromes found that 
pain specialists from North America, Australasia, and 
Western Europe reported more breakthrough pain 
than did pain specialists from South America, Asia, 
and Southern and Eastern Europe. Th
 us, there is a 
need for specifi c educational initiatives about break-
through pain for all groups of health care profession-
als involved in pain management, since the diagnosis 
and treatment of breakthrough pain should be inde-
pendent from the region in which the patient lives. 
Many patients with cancer-related pain are inad-
equately managed, and this problem relates to treat-
ment of both background pain and breakthrough pain. 
Unsatisfactory treatment of breakthrough pain relates 
to inadequate assessment, inadequate use of available 
treatments, and, in many instances, inadequate treat-
ments. Health care professionals need to be aware of 
the diff erent treatment options, and patients need to 
have access to all of these diff erent treatment options 
(e.g., anticancer treatment, nonpharmacological inter-
ventions, and pharmacological interventions).
What are the causes                            
of breakthrough pain?
Breakthrough pain appears to be more common in pa-
tients with
• Advanced disease;
•  Poor functional status;
•  Pain originating from the vertebral column and to 
a lesser extent from other weight-bearing bones 
or joints;
•  Pain originating from the nerve plexuses and to a 
lesser extent from nerve roots.
Other categories include idiopathic break-
through pain, which occurs spontaneously, and break-
through pain known as “end of-dose failure,” which 
typically occurs at the end of the dosage interval of pain 
medication used to control the patient’s persistent pain. 
Th
  is transitory increase in pain should be greater than 
of moderate intensity (e.g., “severe” or “excruciating”). A 
widely used set of diagnostic criteria for breakthrough 
pain is by Russell Portenoy, from Memorial Sloan-Ket-
tering Cancer Center, New York. Th
  e criteria are:
• Th
  e presence of stable analgesia in the previous 
48 hours
• Th
 e presence of controlled background pain in 
the previous 24 hours (i.e., average pain intensity 
of no more than 4 out of 10 on a numeric rating 
scale [NRS])

Breakthrough Pain, the Pain Emergency, and Incident Pain
279
• Temporary fl ares of severe or excruciating pain in 
the previous 24 hours
How is breakthrough pain assessed?
Currently, there is no validated assessment tool for 
breakthrough pain, but the assessment of breakthrough 
pain should involve:
•  Taking a pain history
•  Examining the painful area
• Appropriate investigations.
•  Assessment of pain intensity with well-known 
tools: e.g., verbal rating scale or numerical or vi-
sual analogue scale)
How can breakthrough pain            
be managed?
As always, the best strategy for treatment of break-
through pain would seem to be treatment of the cause 
of the pain, but unfortunately, most of the time, a 
cause of pain that could be eliminated immediately is 
not apparent.
Breakthrough pain is a heterogeneous condi-
tion, and its management therefore may involve the 
use of a variety of treatments, rather than the use of 
a single, standard treatment. Th
 e most appropriate 
treatment(s) will be determined by a number of dif-
ferent factors, including the etiology of the pain (e.g., 
cancer-related, non-cancer-related), the pathophysi-
ology of the pain (e.g., nociceptive, neuropathic), the 
characteristics of the pain (e.g., episode duration), the 
characteristics of the patient (e.g., performance sta-
tus), the acceptability of diff erent interventions, the 
availability of diff erent interventions, and the expense 
of diff erent interventions.
First, you should evaluate whether break-
through pain may be lessened by nonpharmacological 
methods, such as repositioning or bed rest, rubbing or 
massage, application of heat or cold, and distraction and 
relaxation techniques. Also, never forget to check the 
fullness of the bladder in cases of acute pain exacerba-
tion in the lower abdominal region, especially in non-
communicating or sedated patients.
Unfortunately, there is relatively little evidence 
to support the use of these interventions in the treat-
ment of breakthrough pain episodes.
Second, if pharmacological intervention is es-
sential, the drug class of choice in nociceptive pain 
(described as aching, dull, and drilling) is opioids. 
Depending on the intensity of pain, the route of ap-
plication is chosen. In “excruciating” pain (NRS score 
of 9–10), the time interval between an oral opioid and 
pain reduction would be considered to be too long (usu-
ally 30 to 45 minutes) and intravenous (i.v.) titration of 
an opioid would be indicated (usually 5–10 minutes). In 
moderate to high pain (NRS score of 6–8), oral opioids 
may be used. All immediate-release opioids are suitable 
as i.v. or oral breakthrough pain medications.
It is a good idea to combine opioids with nono-
pioid analgesics such as metamizol, ibuprofen, or diclof-
enac, if the patient is not already taking them regularly.
Practical questions about 
breakthrough pain
I am afraid of respiratory depression. Is 
worrying about this typical opioid side         
eff ect justifi ed?
Pain is an antagonist for all depressing eff ects of opi-
oids. As long as the pain and the opioid dose are bal-
anced, there will be only tolerable sedation and no 
respiratory depression. Since the principle of break-
through pain management is opioid titration, this bal-
ance between pain intensity and opioid side eff ects 
can be found easily. Th
  e goal of titration is not no pain 
(NRS score of 0), as at the doses required, side eff ects 
would prevail, but a tolerable pain level (NRS score of 
3–4). Th
  en respiratory depression should not be a ma-
jor concern. However, in rare instances, pain intensity 
may not change, but the patient may become more and 
more sedated. In these extreme situations, the patient 
must be woken up to be able to tell you that the pain is 
still excruciating.
How can a patient be heavily sedated,                
but still in excruciating pain?
Th
  e explanation is that a patient can have pain that is 
not “opioid sensitive,” meaning that because of the type 
of pain (e.g., neuropathic pain) or tolerance eff ects (rap-
id dose escalation with opioids prior to breakthrough 
pain), the opioids are not working. Th
  erefore, the pa-
tient is only experiencing the side eff ects of the opioids.
Alternative techniques to relieve the pain have 
to be considered. In neuropathic pain, oral carbam-
azepine or oral/i.v. phenytoin might work, otherwise 
i.v. ketamine or S-ketamine in analgesic doses might 
be indicated (0.2–0.4 mg/kg or 0.05–0.2 mg/kg body 

280
Gona Ali and Andreas Kopf
weight per hour, respectively). If an anesthesiologist is 
available, regional or neuraxial blocks using catheters 
should be evaluated.
In practical terms, what can I do to help              
a patient in acute excruciating pain?
In general, we never know what the necessary total 
dose for pain control will be. Th
  erefore, the basic prin-
ciple of breakthrough medication application is “titra-
tion.” A young, male, athletic patient with excruciating 
pain may need only 2.5 mg i.v. morphine, while a frail 
elderly lady may need 25 mg of i.v. morphine to get the 
same pain relief.
If your patient has no prior continuous opioid 
medication, 2.5 mg of morphine (or 50 mg of tramad-
ol, 0.5 mg of hydromorphone, or 50 mg of meperidine) 
would be an adequate i.v. titration step. By asking the 
patient each time, 5–10 minutes after the opioid appli-
cation, about pain intensity, you can decide whether ti-
tration has to be continued.
If your patient has a prior continuous opioid 
medication, the titration dose should be around 10–15% 
of the daily cumulative dose of the opioid. If your pa-
tient is on 40 mg oral morphine q.i.d. (total daily dose 
160 mg orally, which would equal 50 mg of i.v. mor-
phine), the i.v. titration dose would be 5–7.5 mg. Th
 e i.v. 
dose may be repeated about every 8 minutes to allow it 
to completely take eff ect before you decide whether fur-
ther titration is indicated. Breakthrough pain analgesic 
titration is considered successful when pain intensity is 
at or below an NRS score of 4.
In practical terms, what do I do in strong,       
but not excruciating, pain?
Basically, the same rules apply as in the last paragraph, 
but instead of i.v. titration, oral titration is used. Again, 
10–15% of the total daily dose is calculated, and that ti-
tration dose is off ered to the patient every 30 minutes 
until pain intensity is under control.
Can I use the acute titration dose to estimate 
the future opioid needs of my patient?
Yes, in cancer patients you can pretty well foresee 
the future opioid demand of your patient. If the pa-
tient needs 30 mg of oral morphine or 10 mg of i.v. 
morphine for analgesic titration, he or she will have 
an estimated daily supplemental demand of 120 mg 
(oral) or 30 mg (i.v.) morphine (corresponding to the 
average duration of action of morphine of around 6 
hours times four, which would equal the supplemen-
tal daily dose).
In what situations may other drugs be  
indicated for breakthrough pain?
Typical indications for other nonopioid medication in 
breakthrough pain would be spasmatic pain or neural-
gic pain.
Spasmatic pain, e.g., from the renal tract, may 
be relieved by relatively high doses of metamizol (2.5 g 
slowly i.v.), which is the fi rst choice of drug.
Neuralgic pain exacerbations, such as in trigem-
inal neuralgia, are best treated acutely with fast-release 
carbamazepine (200 mg).
On rare occasions of refractory neuropathic 
pain, e.g., in Pancoast cancer (superior sulcus tumor 
with infi ltration of the brachial plexus, fi rst described by 
the American radiologist Henry Pancoast), i.v. titration 
of phenytoin might be indicated (5 mg/kg body weight 
over 45 minutes, repeated no more than twice).
However, there is relatively little evidence to 
support the use of these interventions in the treatment 
of breakthrough pain episodes.
Should I always wait until my patient has 
breakthrough pain?
Defi nitely not! All drug regimes for cancer patients should 
include a breakthrough pain medication from the start. As 
a rule of the thumb, the patient should be allowed to use 
extra (“demand”) doses of his regular opioid as needed. In 
a patient with 40 mg oral morphine q.i.d. (160 mg daily), 
the patient should be instructed to take an extra dose of 
20 mg morphine when needed. Th
  e minimum time inter-
val between two demand doses should be 30 minutes to 
allow the eff ects of morphine to develop fully.
Can I use the average number of daily demand 
doses to estimate the true opioid requirement 
of my patient?
Yes. If your patient needs fi ve demand doses daily, you 
should add the cumulative daily demand dose to the 
“background” medication. A patient with 40 mg q.i.d. 
morphine needing morphine demand doses of 10 mg 
fi ve times daily should receive from now on 50 mg q.i.d. 
regularly. A frequency of fewer than four demand dos-
es daily is considered to be “normal,” and therefore the 
dosing scheme may be maintained. If there is no need 
for demand doses, maybe a (small) reduction of “back-
ground” medication may be tried.

Breakthrough Pain, the Pain Emergency, and Incident Pain
281
What are practical considerations for 
breakthrough pain in my patient?
•  Breakthrough pain refers to a cancer patient who 
has a chronic pain problem, and is generally tak-
ing a long-term analgesic to treat his pain, but 
still has episodes of increased pain additional to 
his constant pain.
•  Breakthrough pain in noncancer pain is a diff er-
ent story. Usually breakthrough pain has a dif-
ferent etiology than in cancer pain since there is 
no obvious continuous tissue destruction. Th
 ere-
fore, the patient should not receive “free access” 
to demand doses to avoid dose escalations in pain 
etiologies where long-term analgesia by opioids 
is very rare, e.g., chronic back pain or headache. 
An exception to the rule would be infl ammatory 
pain, as in advanced rheumatic arthritis or sys-
temic scleroderma.
• Not surprisingly, the pathophysiology of the 
breakthrough pain is often the same as that of the 
background pain. Th
  us, breakthrough pain may 
be nociceptive, neuropathic, or of mixed origin.
•  Breakthrough pain may result in a number of oth-
er physical, psychological, and social problems. 
Indeed, breakthrough pain has a signifi cant nega-
tive impact on quality of life. Th
  e degree of inter-
ference seems to be related to the characteristics 
of the breakthrough pain. Breakthrough pain is 
associated with greater pain-related functional 
impairment, worse mood, and more anxiety.
• Th
  e characteristics of breakthrough cancer pain 
vary from person to person, including the dura-
tion of the breakthrough episode and possible 
causes. Generally, breakthrough pain happens 
fast, and may last anywhere from seconds to 
minutes to hours. Th
  e average duration of break-
through pain in some studies was 30 minutes. 
Breakthrough pain episodes have the following 
four key features: high frequency, high severity, 
rapid onset, and short duration.
•  Rescue medication should be taken at the fi rst 
sign of breakthrough pain. Pain that is allowed to 
build up is much harder to control. It is possible 
to experience breakthrough pain just before or 
just after taking the regular pain medication.
•  Medications used for treating breakthrough pain 
are called rescue medications. Th
  ey are the cor-
nerstone for the management of breakthrough 
pain episodes. Rescue medication is taken as re-
quired, rather than on a regular basis: in the case 
of spontaneous pain or nonvolitional incident 
pain, the treatment should be taken at the onset 
of the breakthrough pain; in the case of volitional 
incident pain or procedural pain, the treatment 
should be taken before the relevant precipitant of 
the pain. In many patients the most appropriate 
rescue medication will be a normal-release (“im-
mediate-release”) opioid analgesic.
•  Alternative routes of administration and lipophil-
ic opioids would appear to be appropriate for pa-
tients with insuffi
  cient breakthrough pain control. 
Oral transmucosal, sublingual, and intranasal fen-
tanyl, which has become available in some coun-
tries, would be a good choice for all patients for 
whom the onset of eff ect of oral morphine is too 
slow and the duration is too long.
•  Another type of pain similar to breakthrough 
pain is incident pain. It may be that certain ac-
tivities your patient does during the day are go-
ing to lead to more pain. Your patient needs to be 
prescribed medications for this kind of activity, 
to be taken before engaging in this extra activ-
ity. Th
  e other type of pain that is somewhat like 
breakthrough pain, but is a bit diff erent, is called 
end-of-dose failure. Th
 ese patients are taking 
an analgesic that becomes ineff ective after a few 
hours, and then pain returns. Th
  e answer to that 
problem is to choose a diff erent—longer-acting—
agent, choose a higher dose of the same agent, or 
change the dosing interval to avoid low serum 
levels with consecutive “end-of-dose” failure.
Pearls of wisdom
•  About one-half to two thirds of patients with 
chronic cancer-related pain also experience epi-
sodes of breakthrough cancer pain.
•  Almost all people experiencing chronic cancer 
pain should receive pain medications for around-
the-clock pain control AND a medication specifi -
cally for treatment of breakthrough pain. If you 
have not off ered this option to your patients, al-
ways do so from now on.
•  Morphine (oral and i.v.) is commonly used and 
available. Although it has a delayed onset of ac-
tion, and a prolonged duration of eff ect,  studies 

282
Gona Ali and Andreas Kopf
show that the majority of patients have suffi
  cient 
breakthrough pain control with this approach.
•  As patients learn that certain actions cause break-
through pain, these episodes can be anticipated, 
which may allow patients and physicians to either 
prepare a treatment response or to treat prophy-
lactically.
•  Raising the continuous “background” analgesia 
dose moderately may reduce the frequency and 
intensity of breakthrough pain episodes.
• Th
  e management of breakthrough pain is the art 
of assessment, treatment, and reassessment.
References
[1]  Fallon M, Zeppetella G, Poulain P, Stein C. Realising unmet needs in 
breakthrough pain. Eur J Palliat Care 2007;14: 29–31.
[2]  Mercadante S, Radbruch L, Caraceni A, Cherny N, Kaasa S, Nauck F, 
Ripamonti C, De Conno F; Steering Committee of the European Asso-
ciation for Palliative Care (EAPC) Research Network. Episodic (break-
through) pain. Consensus conference of an Expert Working Group of 
the European Association for Palliative Care. Cancer 2002;94:832–9.
[3]  Mercadante S, Villari P, Ferrera P, Casuccio A. Optimization of opioid 
therapy for preventing incident pain associated with bone metastases. J 
Pain Symptom Manage 2004;28:505–10.
[4]  Portenoy RK, Bennett DS, Rauck R, Simon S, Taylor D, Brennan M, 
Shoemaker S. Prevalence and characteristics of breakthrough pain in 
opioid-treated patients with chronic noncancer pain. J Pain 2006;7:583–
91.
[5]  Portenoy RK, Payne D, Jacobsen P. Breakthrough pain: characteristics 
and impact in patients with cancer pain. Pain 1999;81:129–34.
[6]  Zeppetella G, O’Doherty CA, Collins S. Prevalence and characteristics 
of breakthrough pain in cancer patients admitted to a hospice. J Pain 
Symptom Manage 2000;20:87–92.
Websites
www.pain.com
www.breakthroughpain.eu

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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
Josephine M. Th
  orp and Sabu James
Chapter 37
Pain Management in the Intensive Care Unit
Case report
A 52-year-old man, Joe Blogg, was admitted to the in-
tensive care unit (ICU) from the operating room, after 
undergoing a long surgical procedure. He had been the 
driver of a car that was involved in a head-on collision, 
and he was trapped in the car (no seat belt or air bag) 
for about 30 minutes. When fi rst assessed in the receiv-
ing accident and emergency care unit, he was rousable 
but confused and in considerable pain. His injuries 
were as follows:
Bilateral pneumothoraces (intercostal drains 
were inserted in the accident and emergency unit by the 
resuscitation team). Fractures of the third, fourth, and 
fi fth ribs on the left side. Deep wounds to right knee and 
right elbow, extending to the joint. An extensive mesen-
teric tear, for which he underwent a 5-hour laparotomy. 
Estimated blood loss of about 5 L, coagulopathic, with a 
platelet count of 50,000 postoperatively. He had several 
units of blood and blood components in the operating 
room. He is anuric and hypothermic (with a core tem-
perature of 34°C).
He was transferred to the intensive care unit for 
elective ventilation and management
.