Event 1: Case Summary

CA is a 48-year-old female patient who is status post left total knee replacement arthroplasty under a general anesthetic. Patient had an uneventful operation and had received Fentanyl 250 mcg plus morphine sulfate 10mg iv, in divided doses, throughout the 2hr operation.

In the post-anesthesia care unit (PACU), the patient received a total of: fentanyl 300 mcg for c/o knee pain (NRS 7/10) and lorazepam 0.5 mg for upper leg muscle spasm with reported good analgesic-clinical response.

Patient Controlled Analgesia (PCA) was initiated in PACU with morphine 1 mg/per self-administered injection, 10 minute lock out, no basal rate. Maximum hourly dose allowed each hour = 6 mg. Pt received a total of 12 mg / 2 hr PACU stay.

The patient was then transferred to the ward.

Past Medical History

  • Depression
  • Chronic Knee pain
  • Allergies/Intolerances:
  • Hydromorphone (Dilaudid) > Altered Mental Status

Home Medication History

  • Sustained-release morphine 30 mg po q 12 hours
  • Hydrocodone/ acetaminophen 5/325 mg po every 4-6 hours prn pain
  • Ibuprofen 600 mg po every 6 hours prn pain
  • Venlafaxine XR 75 mg p.o. twice daily
  • Lorazepam 2 mg p.o. at bedtime as needed for sleep

Social History

Denies alcohol or recreational drug abuse

Physical Exam prior to discharge from PACU

Vital Signs

BP 140/86  Hr 90  RR 16  SatO2  99% (2 l NC O2)

Pain NRS

4/10 at rest

Location of Pain

Surgical site: L knee

Quality of Pain

Sharp and throbbing

Pharmacist evaluation of medications received in the PACU


  • Was the patient educated on the use of PCAs prior to anesthesia?
  • Is the patient opioid tolerant or opioid naïve?
  • Are short-acting medications being used for management of acute pain?
  • Is there a risk of dose stacking/drug accumulation? Vs. Is the patient being re-dosed often enough to manage pain?
  • Is patient/regimen being re-assessed appropriately?
    • For pain management
    • For monitoring surrounding analgesia, sedation
  • Long acting opioids may be appropriate to continue, but not initiate
  • Initiation of fentanyl patches are inappropriate and UNSAFE under acute post-operative conditions
  • Use of some adjunctive medications (e.g., TCAs,  antidepressants) may not have immediate effects for post operative pain control
  • Opioids plus benzodiazepines cause sedation
  • Is there a role for other analgesics less likely to cause sedation (e.g., NSAIDs, acetaminophen)
  • Overall, is drug therapy / dosing regimen appropriate?

Opioid Analgesic Pharmacology

Morphine, Hydromorphone and Fentanyl are the most common intravenous opioid analgesics administered in Medical Centers across the USA.

Although they may differ in intravenous potency compared with Morphine

  • Hydromorphone : Morphine (1:5 - 1:8)
  • Fentanyl : Morphine (1:100)

All three opioids bind to the Mu opioid receptor that is principally responsible for their analgesic action.

Currently, there is no widely accepted evidence that morphine, hydromorphone or fentanyl differ in their analgesia or have fewer side effects across a general patient population. However, individuals may exhibit dramatically different responses both in analgesia and adverse effects.

Opioid Analgesic Pharmacokinetics

Intravenous administration of morphine or hydromorphone typically reach peak plasma concentrations within 15 minutes whereas Fentanyl may achieve peak levels at an earlier time point but may have a shorter duration of analgesia.

Delivery of intravenous opioids such as morphine, hydromorphone or fentanyl by  “Patient Controlled Analgesia-PCA”  may have widely differing analgesic and /or adverse effects on individual patients including life threatening respiratory depression.

Opioid Analgesic Pharmacokinetics & PCA Safety

Determination of PCA dose and lock-out interval must be individually considered based on a patient’s prior opioid use and response, underlying hepatic and renal function and underlying respiratory conditions – especially obstructive sleep apnea (OSA).

Although a ten minute lock–out interval, adopted by a consensus practice group (PCA Tool Box – San Diego, CA Hospital Consortium 2011) may provide the benefit of improved patient satisfaction and maintaining analgesia, a ten minute lock out interval with the use of morphine or hydromorphone may still  lead to “dose stacking”  and unintended excesses in opioid administration.

Vigilance  in monitoring for sedation and respiratory depression is essential and continuous measures of pulse oximetry are being adopted as a safety net in the use of PCA – based opioid administration.

Question: Which of the following medications are considered  “non-opioid” analgesics?

Hydromorphone (Dilaudid)


Sustained-release morphine














Three Clinically Relevant Drug-Drug Interactions Found in the Patient’s  Home Medication List

Sustained-release morphine with Hydrocodone

Concurrent use of multiple opioids can cause additive CNS depression increase risk of sedation or respiratory depression 

Sustained-release morphine and hydrocodone (opioids) with Lorazepam (benzodiazepine)

Can cause synergistic CNS depression and respiratory depression. Patients should be monitored closely for signs and symptoms of CNS depression. 

Venlafaxine (SNRI) plus ibuprofen (NSAID)

Use of seretonin reuptake inhibitors, such as venlafaxine, a serotonin-norepinephrine reuptake inhibitor, with an NSAID ibuprofen leads to an increased risk of upper gastrointestinal (UGI) bleeding.  Patients should be educated on the signs and symptoms of UGI when taking these drugs concurrently.  

OPIOID TOLERANCE and DEPENDENCE: The Limits of Opioid-Based Analgesia

With frequent administration of therapeutic doses of opioid analgesics (such as morphine, hydromorphone, fentanyl or other surrogates) a gradual loss of analgesic effectiveness is observed. This loss of opioid-induced analgesia and the requirement to administer larger doses of opioids to achieve the original analgesic response is termed "tolerance."

Typically, along with tolerance, physical Dependence also develops – as evidenced by so called “withdrawal or abstinence syndrome” occurring when a frequently administered opioid is stopped.

The Food and Drug Administration has indirectly defined “opioid tolerance” as a patient that consumes at least  60mg of oral morphine equivalents per day for a minimum of 7 days. This definition emerged as a qualification to initiate a  fentanyl patch at 25 mcg/hr.

A patient taking frequent opioids who has developed Tolerance presents at least two clinical challenges in the setting of pain management

Usual dosing of opioid analgesics may have little to no analgesic effect.

Abrupt termination of scheduled doses of opioids, as may have occurred due to fasting instructions in preparation for surgery and/or advancing illness will trigger a withdrawal syndrome, exacerbating pain, hyperalgesia, restlessness, and enhanced sympathetic drive (e.g., increased heart rate, blood pressure, breaths per minute).

Although poorly understood, opioid tolerance may in part be managed by NMDA receptor antagonists such as ketamine, and withdrawal syndromes treated with alpha-2 receptor agonists , such as clonidine. 

One Hour after Arrival to Ward

The patient arrived to the ward using morphine PCA but complains of worsening (7/10) then uncontrolled L knee pain (10/10) and is restless. Review of administered morphine hourly dose shows that PCA maximal allowable dose has been reached (6 mg/1 hour).

Question: Which of the following detail(s) best help explain this patient’s worsening  pain following transfer to the ward?

Patient failed to take home sustained release morphine while NPO (previous 2 doses) and it has not yet been restarted.


Patient’s preoperative Pain (NRS) Score at rest was 3/10.


Patient is receiving morphine rather than hydromorphone.


Examination of PCA log shows 24 attempted self administered morphine injections with 6 successful administrations each hour.



Patient failed to take home sustained release morphine while NPO (previous 2 doses) or continue post operatively: patient is possibly experiencing opioid  withdrawal, opioid tolerance.

Examination of PCA log shows 24 attempted self-administered morphine injections with 6 successful administrations each hour. Demand morphine dose insufficient to sustain analgesia. The number of patient-PCA - attempts for self-administration (24 / hr) greatly exceeds successful injections 6/hr).

Change in Analgesic Plan

  • The patient was restarted on her home medications (except for ibuprofen).
  • Analgesic orders include adding the patient’s home:  “around the clock” sustained release morphine 30mg PO every 12 hrs, plus hydrocodone / acetaminophen “as needed” PRN  for pain.
  • PCA Morphine demand dose was increased from 1 to 2 mg/ injection with a 12 mg/hr maximum / hr.

Pain reassessment: Following analgesic plan change “pain at rest” reported as 4/10 (acceptable to patient).

Patient instructed to begin mobilization with assistance of nurse and physical therapist.

University of California, San Francisco
University of California, San Francisco