Pain Management

School of Pharmacy
Lebanese International University
Pharmacotherapeutics VI
(Hematology/Oncology)
 Introduction
Pain
 Most common symptoms associated with cancer
 Defined as sensory and emotional experience associated
with actual or potential tissue damage
 Occurs in
 One quarter of patients with newly diagnosed malignancies
 One third of patients undergoing treatment
 Three quarters of patients with advanced disease
 One of the symptoms patients fear most
 Unrelieved pain denies their comfort and greatly affects
their activities, motivation, and quality of life

2
 Introduction
For effective assessment and treatment for cancer related
pain, the physician must be familiar with:
 Pathogenesis of cancer pain

 Pain assessment techniques

 Common barriers to the delivery of appropriate analgesia

 Relevant pharmacologic, anesthetic, neurosurgical, and

behavioral approaches to the treatment of cancer pain

3
 Introduction
World Health Organization (WHO) Algorithm
 Cancer pain ladder

 Patients with pain be started on acetaminophen or NSAID

 If this is not sufficient, the patient should be escalated to a

“weak opioid,” such as codeine

 Subsequently to a “strong opioid,” such as morphine

4
 Introduction
NCCN Guidelines Recommendations
 Patients must be screened for pain at each contact
 Pain intensity must be quantified by the patient
 A formal comprehensive pain assessment must be
performed
 Reassessment of pain intensity must be performed at
specified intervals to ensure that the therapy selected is
having the desired effect
 Psychosocial support
 Specific educational material

5
 Pathophysiologic Classification
 Pain classification includes differentiating between
 Pain associated with tumor

 Pain associated with treatment

 Pain unrelated to either

 Mechanisms of pain pathophysiology

 Nociceptive

 Neuropathic

6
 Pathophysiologic Classification
Nociceptive Pain
 Result of injury to
 Somatic and/or
 Visceral structures

 Nociceptors are present in

 Skin
 Viscera
 Muscles
 Connective tissues

7
 Pathophysiologic Classification
Nociceptive Pain
 It is divided into
 Somatic Pain
 Sharp, well localized, throbbing, and pressure-like
 Occurs after surgical procedures or from bone metastasis

 Visceral Pain
 More diffuse, aching, and cramping
 Secondary to compression, infiltration, or distension of
abdominal thoracic viscera

8
 Pathophysiologic Classification
Neuropathic Pain
 Results from injury to the peripheral or central nervous
system (CNS)
 Symptoms
 Burning, sharp, or shooting
 Occurs due to
 Spinal stenosis
 Diabetic neuropathy
 Adverse effect of chemotherapy (eg, vincristine) or radiation
therapy

9
 Comprehensive Pain Assessment
 A comprehensive evaluation is essential to ensure proper
pain management

 Failure to adequately assess pain frequently leads to poor

pain control

 Algorithm begins by screening all cancer patients:

 During the initial evaluation
 At regular follow-up intervals
 Whenever new therapy is initiated

10
 Comprehensive Pain Assessment
If pain is present on a screening evaluation
 Pain intensity must be quantified, by the patient
(whenever possible)
 Patient’s self-report to pain is the current standard of care for
assessment
 Intensity of pain should be quantified using:
 Numerical rating scale (0-10 )
 Categorical scale: 1-3; 4-6; 7-10
 Pictorial scale (e.g., the faces pain rating scale)
 Children, elderly, non verbal patients

11
 Comprehensive Pain Assessment

12
 Comprehensive Pain Assessment
Patient should be asked to describe
 Characteristics of their pain
 Ex: aching, burning, etc

 Pain History
 Onset
 Duration
 Course

13
 Comprehensive Pain Assessment
Patient should be asked to describe
 Pain Intensity
 Pain experienced at rest
 Pain with movement
 Pain interfere with activities

 Location
 Referral pattern
 Radiation of pain

 Associated factors that exacerbate or relieve the pain

14
 Comprehensive Pain Assessment
Patient should be asked to describe
 Current pain management plan
 Patient’s response to current therapy
 Prior pain therapies

 Psychosocial factors

 Risk of addiction

 Cultural beliefs toward pain

Physical examination and review of appropriate laboratory
and imaging studies

15
 Management of Cancer Pain
Algorithm Distinguishes
 Three levels of pain intensity

 Mild pain (1-3)

 Moderate pain (4-6)

 Severe pain (7-10)

16
 Management of Cancer Pain
Algorithm Distinguishes
 Pain related to an oncologic emergency from pain not
related to an oncologic emergency
 Oncologic emergency; such as pain due
 Bone fracture
 Infection
 Obstructed or perforated viscous (acute abdomen)

 Pain related to anticipated procedure and anxiety

17
 Management of Cancer Pain
Algorithm Distinguishes
 Intake of opioids
 Taking opioids chronically (opioid tolerant) versus not
(opioid naïve)
 Opioid tolerant: patients are taking at least: 60 mg oral
morphine/day or an equianalgesic dose of another opioid
for one week or longer
 Opioid naïve: patients who are not chronically receiving
opioid analgesic on a daily basis and therefore have not
developed significant tolerance.
 patients who do not meet the above definition of opioid
tolerant

18
 Management of Cancer Pain
 Management approach of all levels of cancer pain
involves:
 Use of non-opioidal analgesics

 Consider adding adjuvant analgesics for specific pain

syndrome

 Recognize and treat analgesic adverse effects

 Provide psychosocial support

 Provide patient and family education

 Optimize non-pharmacologic interventions

19
 Management of Cancer Pain
Pain Intensity (1 – 3)
 APAP / NSAIDs
 Consider risk factors associated with increased risk of GI bleeding
before initiation of NSAIDs therapy
 Consider the use of PPIs
 Re-evaluation at each visit or as needed
 Addition of adjuvant analgesics for specific pain syndrome:
example:
 TCAs
 Anticonvulsants
 Bisphosphonates
 Hormonal therapy

20
 Management of Cancer Pain
Moderate Pain (4 – 6) & Severe Pain (7-10)
 Rapidly titrate short-acting opioid
 Begin bowel regimen
 Psychosocial support
 Educational activities
 Re-evaluation within 24 hours
 If pain increased or unchanged ➔ working diagnosis must
be re-evaluated
 The adequacy of opioid titration must be re-evaluated by
calculating & comparing the total morphine dose
administered every day

21
 Selecting an Appropriate Opioid
 Morphine is generally considered the standard starting
opioid of choice

 Other pure opioid agonists such as codeine, oxycodone,

oxymorphone and fentanyl are the most commonly used
alternatives

 Short half-life opioid agonists (morphine, hydromorphone,

fentanyl, and oxycodone) are preferred, because more
easily titrated than the long half-life analgesics
(methadone and levorphanol)

22
 Selecting an Appropriate Opioid
 Hydrocodonne is only available in combination with
acetaminophen (325mg /tablet) or ibuprofen (200
mg/tablet).

 Both methadone and levophanol, due to their long half

life, should be observed for drug accumulation and side
effects after 2 to 5 days

23
 Selecting an Appropriate Opioid
 Transdermal fentanyl
 Not indicated for rapid opioid titration and only for
maintenance
 Transmucosal fentanyl may be considered in opioid tolerant
patients for breakthrough pain

 For patients with renal failure

 Use in caution morphine, codeine, and hydromorphone

 Avoid meperidine
 Risk of neurotoxicity (CNC toxic metabolite)

24
 Miscellaneous Agents
 Avoid mixed agonist-antagonists (e.g.,butorphanol,
pentazocine)
 Limited efficacy
 Precipitate opioid withdrawal crisis if used in patients
receiving pure opioid agonist analgesics

 Tramadol
 Weak opioid receptor agonist with some norepinephrine
and serotonin reuptake inhibition
 Less potent than other opioid analgesics
 Recommended for mild to moderate pain intensities
 Maximal dose (400 mg/day)

25
 Miscellaneous Agents
 Tapentadol
 Mu opioid receptor analgesic with norepinephrine
reuptake inhibition for treatment
 Dose : 50-100 mg q 4 hrs prn max 500-600 mg/day
 Used in moderate to severe pain
 Bupernorphine:
 Partial Mu opioid agonist approved for chronic pain
 Dose 20 mcg/hr transdermal,
 Don’t exceed dose due to risk of QT prolongation
 Ketamine:
 Non competitive NMDA receptor antagonist that block glutamate.
 Non opioid analgesia, may be used as adjuvant.

26
 Route of Administration of Opioid
 Oral is the preferred route of administration for chronic
opioid therapy
 Least invasive, easiest, and safest way
 Peak in 60 minutes

 Continuous parenteral infusion, intravenous or

subcutaneous, for patients who cannot swallow or absorb
opioids enterally
 Produce fast and effective plasma concentrations
 IV Peak in 15 minutes
 SQ Peak in 30 minutes

27
 Methods of Administration
 Around the clock
 Dosing is provided to chronic pain patients for continuous
pain relief
 Regularly scheduled doses

 Rescue dose
 Provided as a subsequent treatment for patients receiving
“around-the-clock” doses
 For pain that is not relieved by regularly scheduled doses

28
 Methods of Administration
 As needed
 For patients who have intermittent pain with pain-free
intervals
 Rapid dose titration is required

 Patient-controlled analgesia technique

 Allows a patient to control a device that delivers a bolus of
analgesic “on demand” according to limited parameters set
by a physician

29
 Management of Cancer Pain
Opioid Naïve Patients (Moderate-Severe Pain)
 Start with an oral dose of 5 to 15 mg of morphine sulfate
or equivalents
 Reassess after 60 minutes to re-quantify the pain intensity
and consider dose adjustments
 Pain score remains unchanged or increase
 Dose should be escalated by 50% to 100% of previous
dose
 After 2 to 3 cycles
 Further increase in the pain intensity; switch to IV
therapy

30
 Management of Cancer Pain
Opioid Naïve Patients (Moderate-Severe Pain)
 Pain intensity scores decreased but inadequately
controlled
 Repeat same opioidal dose
 Reassess after 60 minutes

 Pain intensity scores improved and adequately controlled

 Change dose to prn over initial 24 hours

31
 Management of Cancer Pain
Opioid Naïve Patients (Moderate-Severe Pain)
 Use intravenous dose titrations for patients
 Unable to swallow
 Severe pain, cannot tolerate the short lag time between
injection and oral peak effects
 Inadequate response upon reassessment after 2 to 3 cycles of
the opioids
 Follow same dosing strategies with initial dose of 2 to 5
mg of intravenous morphine sulfate or equivalent
 Assessment is done every 15 minutes

32
 Management of Cancer Pain
Opioid Naïve Patients (Moderate-Severe Pain)

33
 Management of Cancer Pain
Opioid Tolerant Patients (Moderate-Severe Pain)
 Administer opioid dose equivalent to 10-20% of total
opioid taken in the previous 24 h

 Then follow same assessment strategy as opioid naïve

patients

34
 Management of Cancer Pain
Opioid Tolerant Patients (Moderate-Severe Pain)

35
 Management of Cancer Pain
Opioid Naïve/Tolerant Patients
 After 24 hours following up the patient, if acceptable comfort
has been achieved, the total 24 hours dose is to be converted
into a maintenance and breakthrough dosing
 Maintenance dosing through:
 Extended-release oral medication or
 Extended-release formulation (e.g., transdermal fentanyl)
or
 Long-acting agent (e.g., methadone)
 ➔ to provide background analgesia for control of chronic
persistent pain
 Breakthrough dosing:
 Rescue dose of 10% to 20% of the total 24 hours dose,
given on as needed basis, using short acting opioids
36
 Management of Cancer Pain
Treatment for oncological emergency
 Analgesics as specified by above in addition to specific
treatment for oncologic emergency (eg, surgery, steroids,
radiation therapy, antibiotics) as consistent with patient
goals

37
 Procedure Related Pain and Anxiety
 Procedures:
 Wound care

 IV, arterial line, central line injection

 Bone marrow aspiration

 Lumbar puncture

 Skin and bone marrow biopsy

38
 Procedure Related Pain and Anxiety
 Interventions
 Additional analgesics and/or local anesthetics
 Topical local anesthetics creams(containing lidocaine,
prilocaine, tetracaine) applied to intact skin with sufficient
time

 Anxiolytics

 Sedatives/analgesics/general anesthesia

39
 Non Opioidal Analgesia
 High doses of acetaminophen
 Maximum dose 4 g/day but because it is used chronically
(limit to 3 g/day)
and/or

 NSAIDs
 Example: Ibuprofen 400 mg four times a day (maximum
daily dose is 3200 mg/day)
 Caution in patients at high risk for renal, gastrointestinal,
and/or cardiac toxicities, as well as, thrombocytopenia, or
bleeding disorders

40
 Adjuvant Analgesics
 Pain associated with inflammation:
 Trial of NSAIDs or glucocorticoids
 Bone pain without oncologic emergency:
 NSAIDs and titrate analgesic to effect
 Local bone pain:
 Consider local radiation therapy or nerve block (eg, rib
pain)
 Diffuse bone pain:
 Consider trial of bisphosphonates
 Hormonal therapy
 Glucocorticoids and/or systemic administration of
radioisotopes
41
 Adjuvant Analgesics
Neuropathic Pain
 Trial of antidepressant:
 Start with low dose and increase every 3-14 days as tolerated
 Nortriptyline, 10-150 mg/d
 Desipramine, 10-150 mg/d
 Venlafaxine, 37.5-225 mg/d divided in 2-3 doses
 Duloxetine, 30-60 mg/d

42
 Adjuvant Analgesics
Neuropathic Pain
 ± Trial of anticonvulsant:
 Start with low dose and increase every 3-14 days as tolerated
 Gabapentin, 100-1,200 mg three times a day;
 Carbamazepine, 100-400mg two times a day;
 Pregabalin 100-600 mg/d divided in 2-3 doses, or other

 ± Consider topical agents

 local anesthetics including lidocaine patch

43
 Interventional Strategies
Resistant Pain
 Regional infusions (requires infusion pump) of analgesics
(epidural, intrathecal, and regional plexus).

 Neuroablative procedures

 Radiofrequency ablation

44
 Opioidal Adverse Effects
 Most adverse events improve over time, except with
constipation

 Maximize non-opioid and nonpharmacologic

interventions to limit opioid dose and treat adverse effects

 If adverse effects persist, consider opioid rotation

 ➔which involve change from one opioid to an equivalent
alternative

45
 Constipation
Preventive Measures
 Prophylactic medications
 Polyethylene glycol (1 capful/8 oz water PO two times a
day)
 Stimulant laxative ± stool softener (eg, senna ± docusate, 2
tablets every morning; maximum 8-12 tablets per day)
 Increase dose of laxative when increasing dose of opioids
 Maintain adequate fluid and dietary fiber intake
 Exercise if feasible

46
 Constipation
Treatment
 Assess for cause and severity of constipation

 Rule out obstruction

 Titrate stool softener/laxatives as needed with goal of one

non-forced bowel movement every 1-2 d

 Consider adjuvant analgesic to allow reduction of the

opioid dose

47
 Constipation
Treatment
 If persist
 Reassess for the cause and severity of constipation
 Consider adding another agent, such as
 Magnesium hydroxide, 30-60 mL daily
 Bisacodyl, 2-3 tablets PO daily, or 1 rectal suppository
daily
 Lactulose, 30-60 mL daily;
 Sorbitol, 30 mL every 2 h x 3, then as needed,
 Magnesium citrate, 8 oz PO daily
 Polyethelene glycol (1 capful/8 oz water PO two times a
day)

48
 Constipation
Treatment
 Fleet enema, saline, tap water
 Prokinetics as metochlopramide (10-20 mg qid)
 When response to laxative therapy has not been sufficient
for opioid-induced constipation in patients with advanced
illness:
 Consider methylnaltrexone maximum one dose per day

 Consider opioid rotation to methadone or fentanyl

 Consider neuraxial analgesics or neuroablative techniques

49
 Nausea
Preventive Measures
 For patients with a prior history of opioid induced nausea
 Consider antiemetic therapy
Treatment
 Assess for other causes
 Consider
 Prochlorperazine, 10 mg PO every 6 h as needed;
or
 Metoclopramide, 10-20 mg PO every 6 h as needed
or
 Haloperidol 0.5-1 mg every 6 h as needed

50
 Nausea
Treatment
 If nausea persists despite as needed regimen:
 Administer antiemetics around the clock for 1 wk, then
change to as needed
 Consider adding a serotonin antagonists
 Granisetron, 2 mg PO daily; or
 Ondansetron, 8 mg PO three times a day
 Use with caution as constipation is an adverse effect
 Consider Dexamethasone

51
 Nausea
Treatment
 If nausea persists for more than 1 wk
 Reassess cause and severity of nausea

 Consider opioid rotation

 No response :
 Consider neuraxial analgesics or neuroablative techniques

52
 Pruritus
No prevention
Treatment
 Assess for other causes
 Consider antihistamines
 Diphenhydramine, 25-50 mg IV or PO every 6 h; or
 Promethazine, 12.5-25 mg PO every 6 h
 If pruritus persists
 Consider opioid rotation
 Add small doses of mixed agonist-antagonist nalbuphine
 Consider continuous infusion of naloxone, 0.25 mcg/kg/h and
titrate up to 1 mcg/kg/h for relief of pruritus without decreasing
effectiveness of the analgesic

53
 Delirium
No prevention
Treatment
 Assess for other causes
 Consider lowering the dose
 Consider initial titration with haloperidol, or olanzapine or
risperidone

54
 Respiratory depression & Sedation
No prevention
Treatment
 Consider adding of naloxone

55
 Opioid General Principles
 Appropriate dose is the dose that relieves the patient’s pain
without causing unmanageable effects
 Rapidity of dose escalation should be related to the severity of
the symptoms
 Titrate with caution in patients with risk factors such as
decreased renal/hepatic function, sleep apnea, poor
performance status
 According to FDA guidelines, switch from preparations of
opioid combined with other medications (such as aspirin or
acetaminophen) to pure opioid preparation if opioid dose
required would result in excessive (or inadequate) dosing of the
non-opioid component of combination
 Only available combination is hydrocodone with APAP or
ibuprofen

56
 Opioid General Principles
 If patient is experiencing unmanageable adverse effects
and pain is ≤ 3, consider downward dose titration by
approximately 10- 25% and reevaluate.
 ➔Patient would require close follow-up to make sure pain
did not escalate

 Consider opioid rotation if pain inadequately controlled or

persistent adverse effects from current therapy

57
 Principles of Opioid Maintenance Therapy
 For continuous pain, it is appropriate to give pain
medication on a regular schedule with supplemental doses
for breakthrough pain

 Add extended release or long-acting formulation to

provide background analgesia for control of chronic
persistent pain controlled on stable doses of short-acting
opioid
 Total daily dose of new opioid needed by the number of
doses per day to determine the individual dose (eg, 6 doses
for regular PO morphine every 4 hrs; 2 doses for extended
release morphine every 12-h)

58
 Principles of Opioid Maintenance Therapy
 Provide rescue doses of short-acting opioids for
breakthrough pain
 When possible, use the same opioid for short-acting and
extended release forms
 Allow rescue doses of short-acting opioids of 10% to 20% of
24-h oral dose (mg) every 1 h or 2 as needed (prn)
 Ongoing need for repeated rescue doses may indicate a need
for adjustment of regularly-scheduled opioid dose
 ➔Increase dose of extended release opioid if patient
persistently needs doses of as needed opioids or when
dose of around the clock opioid fails to relieve pain at
peak effect or at end of dose

59
 Opioid Conversion
 Determine the amount of current opioid(s) taken in a 24-h
period
 Calculate the equianalgesic dose of the new opioid
 Use table 1
 If pain was controlled on the previous opioid
 New opioid dose must be reduced by 25-50 %
 If pain was not controlled by previous opioid
 may begin with 100% or
 125% of equianalgesic dose (increase by 25 %)

60
 Opioid Conversion
Table 1: Oral and Parenteral Opioid Equivalences

61
 Conversion to Transdermal Fentanyl
 Determine the 24-h analgesic requirement of current
opioid

 Convert to oral morphine

 Consider ratio of 2 mg/d oral morphine: 1 mcg/h of

transdermal fentanyl patch

 Conversion ratio is not to be used for converting from

fentanyl patch to oral morphine

62
 Conversion to Transdermal Fentanyl
 Fentanyl patch is available in 12, 25, 50, 75, and 100
mcg/h
 Avoid more than 3 patched at same time

 Patient should take the last dose of morphine or equivalent

and apply the patch to the skin at the same time

 The fentanyl patch analgesic duration is usually 72 hours

but some patients require fentanyl patch replacement
every 48 hours

63
 Conversion to Methadone
 Calculate the total daily oral morphine dose (or morphine-equivalent
dose) the patient is using

 Based on the oral morphine dose, calculate the oral methadone dose
 Use table 2

 Reduce the calculated equianalgesic dose of oral methadone by at

least 50% to account for incomplete cross-tolerance, dosing ratio
variability, and patient variability

 Divide the total daily oral methadone dose into 3 or 4 daily doses

 Methadone at doses > 300 mg causes QT prolongation. Start

monitoring with ECG at 100 mg/day

64
 Conversion to Methadone
Table 2: Conversion from oral Morphine to Methadone

65
 Example I
A patient is taking 10 mg of sustained-release oral
oxymorphone every 12 hours and needs to be converted
to transdermal fentanyl patch.

Solution

66
 Example II
A patient is taking oral morphine at 30 mg every 4 h and
needs to be converted to oral methadone

Solution:

67