Acute Pain Management  For The Chronic Pain Patient

Prashant A. Patel, MD
Postdoctoral Clinical Fellow
Department of Anesthesiology
Division of Pain Medicine
New York Presbyterian Hospital

Objectives

• Identify perioperative clinical considerations in chronic pain paitents
• Explain the reasons for increased perioperative opioid consumption in the chronic pain patient
• Provide guidelines for periopoerative opioid therapy in the chronic pain patient
• Describe perioperative nonopioid analgesic modalities in the opioid dependent patient

Definition of Acute Pain  in the Perioperative Setting
Pain that is present in the surgical patient because of preexisting disease, the surgical procedure (with associated drains, chest or nasogastric tubes, or complications), or a combination of disease-related and procedure-related sources.
     -ASA Task Force on Acute Pain Management (2004)

Prevalence and Characteristics of Opioid Use for Pain

• Increasing prevalence of opioid use for chronic pain
• From 1999-2003, annual US sales of prescription opioids increased by 130%.
  Opioid prescriptions second only to NSAIDs for pain
• Increased percentage of surgical patients are chronically consuming opioids.

Reasons Behind Increased Number of Opioid Tolerant Patients

• Increased acceptance and prescription of opioid analgesics
• Concerns about analgesic undermedication
• Favorable side-effect profiles of newer semisynthetic and sustained-release opioids
• Morbidity associated with NSAIDs and COX-2 inhibitors

Significance of Postoperative Pain

• 20-30% of patients have moderate to severe post surgical pain.
• Percentage likely higher in chronic pain patients.
• High levels of postoperative pain associated with increased risk of pulmonary and thromboembolic complications.
• Postoperative pain most common reason for delayed discharge after ambulatory surgery. 
• High levels of postoperative pain may be linked to developing chronic pain

Impact of Chronic Opioids on Postop Pain

• De Leon-Casasola et al. (1993):
• 116 surgical cancer patients who received epidural analgesia
• Group 1: patients with chronic opioid consumption (daily morphine dose 90 – 360 mg)
• Group 2: opioid naïve patients.
• 3 times as much epidural morphine used by Gp 1
• 4 times as much IV morphine given for breakthrough pain in Gp 1
• Severity of postoperative pain in Group 1 prolonged need for epidural analgesia by factor of 3 (9 days vs 3 days).

Impact of Chronic Opioids on Postop Pain 

• Rapp et al. (1995): 
• case-controlled retrospective analysis
• 360 patients with malignant or nonmalignant pain
• chronically opioid-consuming patients had increased postoperative pain
• Chronic opioid consuming patients had 3-fold greater postoperative opioid consumption. 

Causes for Increased Opioid Consumption in Patients on Chronic Opioids

• Opioid Induced Hyperalgesia (OIH) – opioid usage of opioids may induce increased sensitivity to pain. 
• Tolerance - increasing amounts of drug required to maintain same pharmacologic effects.

Dose-vs-Response Curve 

• OIH – facilitated nociceptive signaling, resulting in downward shift of opioid dose-vs-response relationship 
• Tolerance - right-shift in opioid dose-vs-response curve.

Opioid-Induced Hyperalgesia 

• Neurobiological changes facilitate nociception leading to hyperalgesia. 
• Maximal during periods of opioid abstinence or in periods between administered opioid doses
• Increased sensitivity to pain, diffuse and generalized
• Reduces analgesic efficacy of subsequent opioids
• Difficult to distinguish from tolerance

Studies Supporting OIH

• Angst MS et al, Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003 
• Hood DD et al, Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg 2003
• Compton et al, Pain intolerance in opioid-maintained former opiate addicts.  Drug Alcohol Depend 2001
• Doverty et al, Hyperalgesic responses in methadone maintenance patients.  Pain 2001

Studies Supporting OIH 

• Two recent controlled studies documented increased postoperative pain and opioid consumption in patients who received a high rather than a low intraoperative opioid dose. 
• Study of women undergoing cesarean section under spinal anesthesia documented increased postoperative opioid consumption if intrathecal opioids rather than saline placebo injected before surgery. 
  Note: Acute tolerance cannot be ruled out .  Tolerance and OIH can coexist. More studies needed to clarify whether both phenomena develop simultaneously and to determine how they are interrelated.

OIH:  Possible Mechanisms

• Sensitization of peripheral nerve endings
• Enhanced descending spinal facilitation of nociceptive signals
• Enhanced production and diminished reuptake of nociceptive neurotransmitters.
• Sensitization of second-order neurons to nociceptive neurotransmitters.

OIH:  Possible Mechanisms 

• Activation of central glutaminergic system, mainly via NMDA receptor 
• Release of spinal dynorphin, a hyperalgesic substance
• Enhanced monoxide signaling (NO/CO)
• Activation of protein kinase C
• Cytokine activation

Opioid Tolerance 

• Loss of effect following repeated treatments such that higher dose is required for equivalent effect. 
• Increasing opioid dose is normal adaptation, NOT harmful addiction.
• Tolerance does NOT develop to miosis or constipation

Opioid Tolerance

• Tolerance develops slower to more potent opioids
• Patients requiring equivalent of greater than 1mg/hr IV morphine or 3mg/hr PO morphine for more than 1 month have high-grade opioid tolerance.
• The higher the daily dose requirement, the greater the degree of tolerance development. 

Two Types of Acquired Tolerance
1)  Pharmacokinetic tolerance
 patients exposed to opioids for long terms metabolize opioids faster 
 Cytochrome P-450 biotransforms opioids
 Cytochrome P-450 inducible by opioids

2)  Pharmacodynamic tolerance 
 related to neuroadaptive changes after prolonged exposure to opioids

Two Possible Mechanisms for Pharmacodynamic Tolerance

1)  Opioid receptor desensitization (classic hypothesis)

2)  Up-regulation of cAMP

Opioid Receptor Desensitization:  Mechanisms
1)  Down Regulation
 Reduced transcription of opioid receptors
2)  Internalization
 Reduction of opioid receptors on cell surface by active endocytosis
3)  Uncoupling of opioid receptors from underlying G proteins

Up-regulation of cAMP 

• Acutely, opiates inhibit cAMP pathway. 
• Chronically, cAMP pathway recovers above baseline and tolerance develops. 
• Up-regulation of cAMP within dorsal horn of the spinal cord likely responsible for tolerance and OIH
• Increased synthesis of cAMP may be responsible for physical dependence and physiologic changes associated with withdrawal. 

Clinical Considerations 

• Lack of randomized controlled studies 
• Not discussed in any major anesthesiology textbook.
• Majority of scientific literature comprised of case reports and expert opinion.

Preoperative Considerations

• Precise opioid use (opioid type, dose, etc) 
• Discuss potential for increased postop pain
• Address patient’s fears and expectations about pain management
• Consider appropriate regional techniques
• Formulate postop pain management plan

Preoperative Medication Considerations:

• Continue preoperative opioid regimen on day of surgery
• Maintain transdermal fentanyl patch perioperatively
• Consider preop adjuvants such as acetaminophen 1000 mg 1 to 2 hours before surgery

Preoperative Medication Considerations: 

• Maintain intrathecal pump opioid infusions throughout perioperative period.   
• Discontinue or reduce intrathecal Baclofen infusion rate.
• Central effects may cause excessive sedation
• Peripheral skeletal muscle relaxing effects may enhance NM blockade

Importance of Maintaining Baseline Opioid

• Opioid dependent patient who required 1000mg of methadone daily did not have her methadone continued perioperatively. 
• Postop, she developed poor pain control and withdrawal symptoms
• Given morphine loading dose of 300mg, followed by  infusion of 100mg/hr. 
• Withdrawal symptoms disappeared, and she experienced good pain control.

Intraoperative Considerations

Administer opioids to meet 3 requirements: 

• chronic, intraoperative surgical, anticipated postoperative.
• Total intraop dose 30-100% greater than for naïve patients
  Consider appropriate regional technique:
• continuous regional techniques preferable
• Local infiltration if other technique not possible.

Intraoperative Considerations
Consider administration of Adjuvant Meds:

• Ketamine 0.5mg/kg IV bolus followed by 4ug/kg/min infusion
• Ketorolac 30mg IV (if NSAID or COX-2 not started preoperatively)
• Acetaminophen 1000mg PR if not started preoperatively.

Acute Postoperative Period

• Aggressive titration of opioids, adjuvant medications, and regional techniques to patient comfort. 
• Use long-acting opioids as opposed to short-acting opioids

Acute Postoperative Period

• Catching up on opioid dose in the postoperative period can be problematic
• Patients with even modest preop opioid use (<50mg/day oral morphine equivalent) will often require their baseline opioid dose plus 2 or more times dose required for opioid-naïve patients.

Postoperative PCA

• If oral route is available, start with 1.5 times the preoperative oral opioid dose and PCA for breakthrough pain. 
• If oral route unavailable, start basal infusion on PCA at rate that is equianalgesic to patient’s hourly oral dose or 1-2 PCA demand doses
• Basal infusion not necessary for patients with fentanyl patch or intrathecal pump

Opioid Rotation 

• Recommended if increasing opioid dose results in increasing side-effects without adequate pain control  
• Incomplete cross-tolerance enables substitute opioid to achieve improved pain control at lower dosage, with fewer adverse effects
• Recommended starting dosing is half to two thirds of dosage estimated from equianalgesic tables

Equianalgesic Table
    Oral (mg) IV (mg)
Morphine   30  10
Hydromorphone  7.5  1.5
Oxycontin   20  -
Oxycodone   30  -
Hydrocodone   30  -
Fentanyl   -  0.1
Oxymorphone   15  1
Codeine   200  130
Meperidine   300  75
Methadone (acute)  10  5
Methadone (chronic)  2-4  2-4

Equianalgesic Dosing 

• Equianalgesic dose table describes relative potencies between different opioids for both oral and IV routes  
• Term “Equianalgesic” used for two doses with comparable pharmacological analgesic effects.
• Equianalgesic Table useful starting point, should only be used to provide rough guidelines

Example
45 year-old woman with metastatic rectal carcinoma scheduled for bowel resection and possible colostomy. 
Preoperative opioid requirement included oxycontin 200mg BID and Percocet (10/325) 2 tabs Q4h PRN (uses about 12 pills per day). 
General endotracheal anesthesia with isoflurane and fentanyl. 
In PACU, patient is awake and alert, in considerable pain 3 hours after her last dose of fentanyl.

Example
First, titrate boluses of opioid to patient comfort.

 Oxycontin is long-acting formulation of oxycodone
 Conversion: 20mg oxycontin = 30mg PO morphine
 400mg oxycontin = 600mg PO morphine = 200mg IV morphine

 One 10/325 percocet tab includes 10mg oxycodone and 325mg Tylenol
 12 tabs = 120 mg oxycodone = 120mg PO morphine = 40mg IV morphine

 200 + 40 = 240 mg IV morphine over 24 hrs

Accounting for incomplete cross-tolerance, baseline opioid requirement would be 240/2 = 120 mg IV morphine over 24 hrs = 5 mg/hr IV morphine
Adequate morphine PCA:  4-5mg basal/2-3mg demand/6-10 min

Regional Techniques & Parenteral Opioids

Opioid tolerant patients should be offered regional anesthesia whenever possible to decrease IV/oral opioid requirements.

Opioid-dependent patients undergoing regional techniques with local anesthetic still need systemic opioids to prevent withdrawal 

Daily systemic administration of at least half of the preoperative opioid dose is sufficient to prevent withdrawal

Neuraxial Opioids

1mg IT morphine = 10mg epidural morphine = 100mg IV morphine
With sole use of neuraxial opioids, plasma concentrations and supraspinal recepetor binding of opioids may decline to the point that acute withdrawal is precipitated.  Therefore, baseline opioid requireents must maintained via oral or IV route.

PACU nurses should be instructed about potential for overdose when IV and neuraxial opioids are administered concomitantly.

In chronically opioid consuming patients, epidural administration of very potent lipophilic opioids such as fentanyl or sufentanyl may be superior to the use of less potent hydrophilic compounds such as morphine (based upon case reports).

Methadone as Adjunct for Postop Pain

• Methadone activates different spectra of opioid receptor subtypes to which morphine tolerance has not developed.
• D-isomer of methadone had NMDA receptor antagonist properties, blocking opioid tolerance and OIH
• Methadone inhibits reuptake of serotonin and norepinephrine 
• Methadone lacks neurotoxic metabolites
• Starting methadone PCA 1.25mg every 10 min.

Ketamine as Adjunct in Opioid-Dependent Patients

• N-methyl-d-aspartate (NMDA) receptor blocker
• Ketamine may reverse opioid tolerance & OIH.
• Initiate ketamine therapy intraoperatively as bolus of 0.25 to 0.5mg/kg followed by an infusion at rate of 2 to 4 ug/kg/min

Ketamine Studies

• Several studies have reported improved postop pain control and reduced postop opioid requirements when ketamine was used. 

Weinbroum (2003):

• 131 postop surgical patients with morphine-resistant pain
• IV subanesthetic ketamine combined with morphine improved pain relief at smaller morphine doses than morphine alone
• Ketamine-treated patients showed better oxygen saturation and greater wakefulness

Additional Adjuvant Medications

• NSAIDS with attention to renal function and risk of bleeding
• Acetaminophen 1000mg every 6hrs
• COX-2 inhibitors
• Oral dextromethorphan, NMDA receptor antagonist, diminished postoperative pain and opioid requirements in several studies when given at doses of 30-90 mg before surgery.
• Gabapentin reduced postoperative pain in 2 clinical studies when administered preoperatively (1200mg) or postoperatively (1200mg/day)

Addtional Adjuvant Medications

• Dexmedetomidine and other alpha-2 agonists such as clonidine may reduce postoperative opioid requirements and pain.  They alleviate opioid withdrawal symptoms as well as pain.
• TCAs (used for neuropathic pain) have small or no effects on postoperative pain.
• Consider contribution of fear and anxiety to overall pain syndrome and treat with appropriate medications such as benzodiazepines as required.

Opioid Antagonists & Partial Agonists

• Opioid antagonists, including naloxone and naltrexone, may precipitate withdrawal symptoms in opioid-dependent patients and should be avoided.
• Mixed agonist-antagonist-type opioids that block mu receptors, such as nalbuphine, butorphanol, and pentazocine, may also precipitate acute opioid withdrawal in chronic pain patients. 

Postop Transition To Oral Opioid Regimen

• Convert daily postop IV opioid dose into an oral-dose equivalent
• Administer 1/2 - 2/3 of this dose as long-acting opioid for baseline pain control
• Administer remainder as short-acting opioid for breathrough pain.
• As surgical pain subsides, cut back on breakthrough medication.
• Tapering patients off their postoperative opioid dose within 2-4 weeks is reasonable goal.

2005 ASRA Acute Pain Summit

• Group of ASRA experts examined 10 practice-based statements.
• Statement 10:  Postoperative pain can be effectively controlled in patients with opioid tolerance.
• Detailed literature search: no controlled data or meta-analysis
• Level of evidence for statement was Category III (evidence obtained from case series, case reports, or flawed clinical trials)
• 0% voted to accept statement completely
• 64% voted to accept statement with some or major reservations
• 36% voted to reject either with reservations or completely

Future Directions

• Need for more RCTs as apposed to case reports
• Need for RCTs that evaluate dose requirements after various surgical procedures in opioid-tolerant patients
• Need for RCTs that evaluate whether multimodal analgesic approaches improve postsurgical outcomes in both short-term and long-term.

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