MSU College of Human Medicine Michigan State University
Home - Learning Objectives
Choose an Opioid
Examples - Changing Meds
Routes of Administration
Examples - Changing Routes
Side Effects
Active Dying Process
Opioid Addiction
Opioid Resistant Pain
Post Test
Links and References

Objective 3: Know the pharmacology relevant to choosing an opioid for pain treatment in terminally ill patients.
A. WHO Ladder Approach [back to top]

The World Health Organization “Analgesic Ladder” was developed to address inadequate pain relief decades ago.  Whether it is still an appropriate model is controversial.  Critics point out that the distinctions between Ste 2 and Step 3 opioids are artificial, based more on the opioid’s availability only in combination products rather than any actual pharmacologic properties

In this model, the selection of the appropriate analgesic therapy is based on the severity of the patient's pain and his/her current analgesic therapy. Pain intensity can be measured reliably in most patients with the use of written or verbal numerical rating scales.

In general, pain that is rated 4-5 or higher on a scale of 0 to 10 interferes with a patient’s quality of life and is considered to be significant pain.

Pain ratings of 1 to 4 correspond to mild pain.
Pain ratings of 5 to 6 represent moderate pain.
Pain ratings of 7 to 10 mark severe pain.

However, many patients use these numbers differently.  For example, someone may have severe pain but rate it as “4” while another person might have mild pain rated as “9.”  Clinical judgment is required, and it may be helpful to clarify the patient’s sense of the pain (without criticizing his/her choice of number):  “I find that many people mean that the pain is pretty mild when they rate it as a “4” – is that true for you as well?”

The Three-Step Analgesic Ladder of the World Health Organization uses these three categories of pain to guide analgesic drug therapy (see figure 1).

Patients receiving no analgesic therapy, who have mild-to-moderate pain should be treated first with nonopioid analgesic drugs (Step 1). If a patient has mild-to-moderate pain despite taking a nonopioid analgesic, the dose of the nonopioid analgesic should be maximized and a step 2 opioid analgesic (a "mild" opioid such as codeine, hydrocodone or oxycodone) should be added. Patients who have moderate-to-severe pain (or pain unrelieved by maximal therapy with Step 2 opioids) require a change to a Step 3 opioid (a "major" opioid such as morphine, hydromorphone or fentanyl).

The Three-Step Analgesic Ladder of the World Health Organization uses these three categories of pain to guide analgesic drug therapy (see figure 1).

Patients with mild-to-moderate pain should be treated first with nonopioid analgesic drugs (Step 1). If a patient has mild-to-moderate pain despite taking a nonopioid analgesic, the dose of the nonopioid analgesic should be maximized and a step 2 opioid analgesic (a "mild" opioid such as codeine, hydrocodone or oxycodone) should be added. Patients who have moderate-to-severe pain (or pain unrelieved by maximal therapy with Step 2 opioids) require a change to a Step 3 opioid (a "major" opioid such as morphine, hydromorphone, oxycodone or fentanyl).

This “step” method can effectively relieve pain in 80 to 90 percent of patients with advanced illnesses.

Note: Many experts recommend a Step 3 opioid as initial therapy for patients with moderate to severe pain in advanced illness. Other argue that this approach may increase side effects. (ahcpr)

B. Nonopioid Analgesics [back to top]

Nonopioid analgesics include acetaminophen, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors.  Patients typically have tried these agents for pain relief before seeking assistance from their physician.

All of these agents have a ceiling effect in analgesia (a maximum dose beyond which analgesic effect does not increase), and all have potential for serious adverse effects.  They also all have an anti-pyretic effect and  do not cause withdrawal symptoms.

Acetaminophen is a useful analgesic whose mechanism of action is poorly understood (inhibition of a COX-3 enzyme has been proposed). Excessive doses can cause serious, even fatal, hepatic injury, and the incidence of such injury has been rising steeply in recent years. The maximum safe dose for chronic administration is currently considered to be 3-4 grams per day.  Many experts recommend a maximum chronic dose of 3 grams, or even less, for elderly patients and those with hepatic impairment.

Acetaminophen does not have any significant anti-inflammatory action or any effect on platelet function.  Use of alcohol with acetaminophen is a significant risk factor for hepatic injury – patients taking maximal doses of acetaminophen should be cautioned to avoid alcohol.  An important although under-recognized interaction with warfarin is an additional concern with use of acetaminophen.

NSAIDs (including aspirin) may also be useful analgesics. They work by inhibiting cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins. In addition to this peripheral effect, data suggests that NSAIDs also work at central action in the brain and spinal cord.

NSAIDs vary in their COX-2 selectivity. COX-2 is the enzyme produced in acute inflammation.  Although COX-2 inhibitors had initially been thought to be safer than COX-1 agents, more recent studies have been demonstrated that all NSAIDs share the same significant adverse effects, though with differing frequency.  These include effects in the following systems:
  • Gastrointestinal:  anorexia, nausea, pain, gastritis, ulcers, bleeding and perforation,
  • Cardiovascular:  including hypertension, myocardial infarction, stroke and other thromoembolic events. 
  • Renal:  sodium and water retention, decreased GFR and renal failure (especially worrisome in patients with CHF, CRF, cirrhosis, HTN, or hypovolemia
  • Central nervous system:  headache, dizziness, confusion, depression, reduced seizure threshold
  • Platelets:  inhibition of platelet aggregation inhibition.

The frequency and potential seriousness of these effects is often under-estimated.  In addition, hypersensitivity reactions are more common than most of us realize – about 1% in otherwise healthy adults and 10-25% in those with asthma, nasal polyps, or chronic urticaria.  These reactions can range from simple vasomotor rhinitis all the way to anaphylaxis.  Cross-reactivity is common, so patients who have had hypersensitivity reactions to one NSAID (most commonly aspirin) have a relative contraindication to trials of others.

The pharmacology of specific NSAIDs is beyond the scope of this module.

C. Opioid Analgesics [back to top]

1. General

In 1682 Sydenham said: "Among the remedies which it has pleased Almighty God to give to man to relieve his sufferings, none is so universal and so efficacious as opium," and this is still true hundreds of years later.

a. Pharmacokinetics

Most of the opioids (with the exceptions of methadone and fentanyl) have similar first order pharmacokinetics. They are conjugated in the liver and excreted (90 ~ 95%) by the kidney. Plasma concentrations are achieved rapidly:

Method of administration

Initial effects (minutes)

Peak plasma concentration(minutes)

Peak effect

Half life




Delayed because of time to cross blood-brain barrier*

3-4 hours**







 *This time varies according to how lipophilic the opioid is.  Fentanyl reaches full effect sooner than any other opioid because of its highly lipophilic nature.

** This half life increases with renal impairment

Most also have pharmacologically active metabolites that are renally cleared but have longer half-lives than the medication itself.  These metabolites vary in clinical significance. The neurotoxic active metabolite of meperidine was described first, but further work has made it clear that both morphine and hydromorphone also have active metabolites with CNS toxicity.  Case reports suggest that this will probably uncovered for fentanyl and methadone as well (although the clinical impact is typically less).

There is no clear evidence about which is the best opioid for patients with marked renal impairment, but many experts recommend methadone and fentanyl as the ones least likely to accumulate in a patient with renal impairment.

b. Dosing: regular and breakthrough

Most patients need regular dosing of an opioid, preferably with a sustained release formulation that simplifies the patient’s regimen. In addition, they need access to "p.r.n." (as needed) or "breakthrough" doses along with their regularly scheduled doses. Few patients have pain that is completely stable and steady; most experience exacerbations that require additional breakthrough dosing at least occasionally.

Regular dosing: The usual intervals for effective regular dosing for specific opioids are included in the Equianalgesic Table.

Fast Fact: Oral Opioid Dosing Intervals

  • Sustained-release dosing:  When a stable 24 hour dose has been achieved with good pain relief, sustained-release preparations should usually be introduced. This will reduce the burden on the patient or caregiver to administer medication so frequently, and it will also provide more stable serum levels, reducing peak-related side effects and trough-related pain (see image).

Advantages of sustained-release dosing

Simply divide the 24 hour total dose by the dosing method of the sustained release medication (usually q 12 hours) to calculate the new regimen. 

For example, after a patient has gotten good relief with regular administration of morphine 30 mg q 4 hours [a 24 hour total of 180 mg: 30 mg x 6(four hour intervals in 24 hours) =  180 mg per 24 hours), the new sustained-release regimen would be 90 mg (180 divided by 2) sustained-release morphine q 12 hours (see image).

Change to sustained-release dosing

  • Breakthrough dosing:  Breakthrough dosing is often confusing to clinicians.  A standard and conservative rule-of-thumb for an initial breakthrough dose is 10% (up to15% is recommended in the literature) of the 24 hour total dose.  Some patients will need higher doses, and checking with the patient about the effectiveness of the dose is very important.  Adjustments in the dose, usually upwards, can be made based on patient feedback.

The intervals for breakthrough doses can be derived from the time to peak effect of the opioid and its route of administration, NOT from the usual interval for regular dosing (a common mistake),  (See “a” above.)  One to one-and-one-half hours is a quite conservative interval for repeat oral dosing for continued pain; and 15-20 minutes is a similarly conservative interval for repeated intravenous dosing. In the case of severe pain, clinical judgment should be used to shorten the intervals for repeat dosing, and the dose itself should be aggressively increased. In many cases, an ongoing need for dosing at short intervals suggests a need for dose increase.  See Equianalgesic Table

There is NO MAXIMUM DOSE for opioids: the opioids have no ceiling effect for analgesia.  Doses are limited only by side effects.

c. Titration 

The pharmacologic principles for titration are the same as those reviewed above in “Dosing.”

The speed (“aggressiveness”) of titration should vary according to the severity of the pain.  For mild or moderate pain, twenty four hour intervals are often adequate for reassessment and titration.  The dose adjustments can be relatively conservative.

For moderate pain, more rapid titration is often appropriate, and severe pain should be regarded as a medical emergency.   Titration can proceed at the time intervals outlined above (or faster), and doses should be reevaluated frequently (as often as the titration dosing interval). 

A rule-of-thumb for dose increases is to use 25-50% more for mild-moderate pain, and 50-100% more for moderate to severe pain. A dose increase of less than 25% is likely to have no effect.

A common mistake in the hospital setting is to increase the rate of a continuous infusion of an opioid without using a bolus dose.  Recalling the principle in pharmacokinetic that it takes 4-5 half-lives of a drug to reach a new steady state, we can readily see that simply increasing the infusion rate will take 10-15 hours to reach a new steady state. (e.g. the new level of analgesia).  This is a seriously delayed response for most patients in the inpatient setting.

Fast Fact: Opioid Infusions
Fast Fact:  Opioid Infusion Titration 
Fast Fact: PRN Analgesic Orders 
Fast Fact: Opioid Dose Escalation

d. Opioid allergies

True allergic reactions to opioids are very rare. Patients often report “allergies” – they should be queried about the specific reaction they had.  Many describe nausea and vomiting; others experienced CNS effects like hallucinations.  (While this may be important information in the treatment plan, it does NOT constitute an allergy and should not be recorded as such.) Many side effects are often confused with allergic reactions, but they are actually adverse effects that are generally easily managed. 

Urticaria, itching and bronchospasm are usually a result of a direct histamine-release effect rather than a true immune-mediated allergy.  Histamine release is more commonly a problem with morphine than with other opioids. It may be effectively treated with antihistamines, or a different opioid may be tried. 

If true allergy is suspected, an opioid from a different chemical class may be tried,and consultation with an allergy expert should be considered.

Fast Fact: Opioid Allergic Reactions   

2. Mild Opioids

This group of opioids is considered “mild” because they are generally available as fixed-dose combination products with aspirin or acetaminophen. When using these products, the toxicity of the non-opioid limits the dose of the opioid that can be administered daily.  Because of this, they are inadequate for moderate to severe pain.  They are also limited by a short duration of action (no sustained-release forms available) and being available in oral forms only.

Codeine - Codeine is the least useful of this group of opioids.  Codeine is a “pro-drug” that must be metabolized to morphine in order to have analgesic effect.  (Interestingly, its cough-suppressing effect is independent of this metabolism.)  Up to 10% of Caucasians do not have the required enzyme for this conversion, and more recent work has suggested that this deficiency may be even more common.

In addition, codeine is the most constipating of the opioids at equianalgesic doses, and many experts believe it also has the highest rate of nausea and vomiting. Finally, analgesic efficacy is quite low – most studies show a minimal increase in pain relief when a patient is given acetaminophen with codeine as compared to acetaminophen alone.  Side effects however are considerably higher with the codeine. Consider just dropping codeine from your pain management options!

Hydrocodone - Hydrocodone is a useful opioid, limited mainly by its availability solely as a combination product (with acetaminophen or ibuprofen).  Physicians should also be aware of its current status as the most commonly abused prescription medication in the US.  (All prescription opioids are subject to abuse.)

Oxycodone - Oxycodone was available only as a combination agent when the WHO developed the ‘Analgesic Ladder’.  However, it has now been available in the US as a single agent in both short and long-acting forms for many years.  It is more appropriately considered now as a “major” opioid.  See below.

3. Major Opioids

Potency, when choosing between the major opioids, recall the concept of “potency.”  This simply means that it takes fewer milligrams of one drug to create the same analgesia as another…. – it does NOT mean that one opioid is superior to another in analgesic effect. 

We have a strong tendency to feel more comfortable giving higher equianalgesic doses of more potent opioids (like hydromorphone) than less potent (like morphine) because the numbers are lower:  1.5 mg hydromorphone equals 10 mg morphine IV.  This “comfort zone” is irrational and awareness of it can help us to overcome this inappropriate tendency.

  • Morphine - is the most commonly used opioid because it is one of the oldest agents and none of the newer ones ever have been shown to be more effective. It is also available in multiple forms, making it easy to titrate and change routes of administration.  Liquid morphine also provides the option for the lowest dosing of any opioid. Sustained release preparations are also available.  In addition, the cost of morphine is the lowest of all the opioids recommended for general use. 

Cochrane review: Oral morphine for cancer pain 

  • Oxycodone - is similar to morphine in most ways. Many experts believe it to have lower GI side effects, although there is no clear evidence to support this opinion.  Some experts feel that oxycodone may be more problematic in patients with hepatic impairment than the other opioids.

It is available in a lower potency oral tablet/capsule form (5 mg) than morphine, which is often helpful in initial therapy for patients with less severe pain or those anticipated to be particularly vulnerable to the effects of dosing too high, such as the elderly.  (Liquid morphine is also an option.)  Sustained release preparations are available in a wide range of doses.

  • Hydromorphone - is pharmacologically very similar to morphine.  It is particularly useful in patients with idiosyncratic reactions or side effects from morphine.  Unfortunately, no sustained-release form of hydromorphone is available yet in the U.S.  Because of its potency (lower dose required to get the same effect relative to other opioids), it can be useful when very high dose treatment is needed, especially sub-cutaneously.  See the warning about misunderstanding of potency above.

  • Fentanyl - is most commonly used as a transdermal product (Duragesic) available in patches that are replaced q 72 hours.  Transmucosal preparations are also available (lozenges) for breakthrough pain relief with more rapid onset of action than other non-parenteral opioids.  Fentanyl is often used intravenously for procedures or for intensive care patients, when its rapid onset and relatively shorter duration of action can be an advantage.  Fentanyl has a somewhat reduced risk for respiratory depression in the acute care setting.   Its strong lipophilic quality is the reason it can be given transdermally and transmucosally.

Fentanyl patches are NOT recommended for use in opioid-naïve patients.

Fentanyl patches are also not recommended for use in titrating opioids.  There is a twelve to eighteen hour delay in onset of action, and the peak is not reached until 18-24 hours or more, so it is NOT an appropriate treatment for acute pain or acute exacerbations of pain.   Remember that there will also be a similar delay in discontinuing the drug after patch is removed because of the subcutaneous reservoir of the medication. Frequent increases in patch strength without titration by another route can produce dangerously high new peak levels on a delayed time frame.

Transdermal absorption varies considerably between patients, and, more importantly, over time in the same patient.  Data are lacking about predicting variations in patients.  Many experts believe that transdermal fentanyl is less effective in elderly patients.  Evidence has recently shown that cachetic patients have lower serum levels of fentanyl from the same dose patch that patients of normal weight, presumably because a lack of subcutaneous fat affects the pharmacokinetics (lack of depot/reservoir site).  Absorption may also vary with skin temperature; high fever theoretically risks toxicity.

  • Methadone - is not recommended for use by the majority of physicians , because it is a difficult drug to manage:
    • It has a long and variable half-life, in addition to a large volume of distribution. 
    • It has active metabolites with even longer half-lives (55 hours), and may take over 2 weeks to reach a steady state after a single dose change. 
    • Accumulation can result in prolonged sedation and difficulty in managing fluctuations in pain.

QT interval prolongation can occur with methadone, and the appropriate clinical management of this risk is controversial. 

It is best prescribed only by experts with experience in its use.   Its appeal includes:

  • its very low cost,
  • potential reduced accumulation in renal failure, and
  • possible superiority for refractory neuropathic pain (it is thought to have NMDA receptor antagonist activity not present in other opioids).
Cochrane review: Methadone for cancer pain
Fast Fact: Methadone - Starting Dose Information
Fast Fact: Methadone for Neuropathic Pain
  • Meperidine (Demerol) - is a poor choice for chronic pain therapy because it has poor oral absorption (<40%), a short duration of action (half-life 3 hours or less), and an active metabolite which is neurotoxic (tremor, dysphoria, seizures).  Many hospitals have removed it from the formulary.

This metabolite, normeperidine, is not analgesic, but it has a longer half-life than meperidine, so it is prone to accumulate.  It is renally excreted, thus particularly problematic with patients with renal compromise (those with known renal disease, elderly patients, etc.).

Fact Fast: Meperidine for Pain -What’s All the Fuss?

g. Other opioids:  Tramadol and buprenorhine will not be discussed here.

D. Equianalgesia Tables [back to top]

Equianalgesia tables are used when switching from one opioid to another, or when switching routes of administration. This helps to reduce problems related to under-dosing or over-dosing. Remember, "equianalgesia" simply refers to how much of drug A is needed to provide the same pain relief as x amount of drug B (note that "potency" refers only to the amount of the drug needed to achieve a given effect, not to its overall ability to relieve pain).

Comparative values are approximate and are achieved by consensus from quite limited evidence. Therefore, you must titrate the new opioid based on the patient’s response when changing opioids. The only one who can really define the equianalgesic dose is the patient.

Charts give values that apply to repeated administration in patients with chronic pain, not to occasional acute use.

IV values should mainly be used when converting from IV to other forms of administration.  If starting IV use, always use small frequent doses and titrate up to clinical effect. This is particularly true when using IV administration because of poor pain control with oral administration (as poor absorption may have contributed to the problem).

If changing opioids because poor pain relief was suspected to be due to tolerance, the standard approach is to reduce the dose by 50% to convert.

Fast Fact: Calculating Opioid Dose Conversions

Dose Equivalents for Opioid Analgesics in Adults  




Usual Oral Dosing Interval Required

Forms Available






30 mg

10 mg

 q 3 - 4 h

Tabs,  Liquid,  Sustained release




Hydromorphone (Dilaudid)

7.5 mg

1.5 mg

 q 3 - 4 h





Meperidine (Demerol)

300 mg

100 mg

q 2 - 3 h






20 mg

10 mg

quite variable








transdermal patches: q 3 days






20 mg


q 3 - 4 h

 Sustained      release





30 mg


q 3 - 4 h






180 -   200 mg


 q 3 - 4 h





*Fentanyl (patches or oral forms) should never be used in opioid naive patients. Use manufacturer's table for dosing after the patient is established on another opioid.

* Meperidine(Demerol) and Codeine are NOT recomended for use as analgesics- see text above    

Next: Examples of Changing Medications


MSU Health Information Technology