Course Content

Introduction

As more than 100 million Americans suffer from chronic pain, it has emerged as the most common cause of long-term disability. Almost 80 percent of patients who experience chronic pain report their pain prevents them from performing activities of daily living (ADLs). As pain management has evolved to become a common aspect in health care, pain is viewed as the fifth vital sign. It is without question that pain is an ailment that health care providers encounter each day, and the impact of pain on the economic health care system continues to grow.

Pain is defined as an unpleasant sensory or emotional experience associated with actual or potential tissue damage or described in terms of such damage. There are several different types of pain including nociceptive and neuropathic. Nociceptive pain is further categorized as somatic pain caused by injury to body tissue that is well defined and localized, or visceral pain caused by injury to the viscera that is poorly localized due to being mediated by stretch receptors. Neuropathic pain follows the nervous system and can be due to damage to a peripheral nerve (peripheral neuropathy), autonomic change (sympathetically mediated pain), or from abnormal central nervous system activity (central pain). Examples of peripheral neuropathy, sympathetically mediated pain, and central pain are diabetic neuropathy, sympathetic dystrophy, and phantom limb pain, respectively. The American College of Rheumatology defines chronic pain as pain lasting longer than three months.

The approach for the treatment of pain, or pain management, should be a multidisciplinary team approach utilizing nonpharmacologic and pharmacologic options. The Institute of Medicine’s Report on relieving pain in America emphasized the need to change the patient and provider’s view of pain. This includes viewing pain as a public health challenge and tailoring pain care to each patient’s experiences. While customizing pain management for each individual patient, the patient’s expectations of pain reduction should not be to become 100 percent pain free, as most clinical trials suggest a 33-50 percent reduction in pain as a reasonable standard to determine if a regimen is effective. Communicating this information to patients is helpful in establishing realistic treatment goals and reduce unnecessary dose escalations.

Non-pharmacologic options should be considered with any pain management plan, including relaxation, aerobic exercise, physical therapy, electric stimulation, and acupuncture. A meta-analysis of 40 systematic reviews comparing a variety of nonpharmacologic options such as acupuncture, back schools, and exercise therapy showed benefit in reducing pain compared to placebo, sham therapy, or no treatment. A randomized study of 120 patients with osteoarthritis of the knee compared acupuncture plus pharmacotherapy, sham acupuncture plus pharmacotherapy and pharmacotherapy alone. The acupuncture plus pharmacotherapy group shows statistically significant improvement in the Western Ontario and McMaster Universities index, which assesses pain, stiffness, and physical function in patients with osteoarthritis. Suggesting alternatives or adjuncts to pain medication, such as exercise and physical therapy can be of great benefit to patients, and community pharmacists can recommend appropriate options for patients when necessary.

Many pharmacologic options exist for the treatment of pain with an outline of escalation from over-the-counter options to high dose opioid therapy using the World Health Organization (WHO) Pain Ladder. Although originally designed for relief from cancer pain, the step-wise approach has been used for relief of chronic non-cancer pain as well. The pain ladder suggests using non-opioids and adjuvants initially including non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, skeletal muscle relaxants, and topical agents. If the pain worsens or remains after use of the above agents, continuation onto opioid therapy is recommended.

Pathophysiology

Classification of Pain

Acute

• Predicted physiological response to stimulus

• Self-limiting

• < 3 months duration

• Associated with surgery, traumatic injury, tissue damage, and inflammation

Chronic

• Intractable pain

• Does not resolve in response to treatment

• ≥ 3 months duration

• Cause may or may not be known

Types of Pain

Nociceptive Pain

• Results from the activation or sensitization of nociceptors located in the periphery

• Categorized as somatic and visceral pain

• Examples include trauma, post-operative pain, lower back pain, arthritis and sickle cell crisis

Somatic

• Excitation and sensitization of nociceptors in bone, peripheral soft tissue, joints, and muscles

• Generally well-localized

• Described as aching, stabbing, gnawing, or throbbing

Visceral

• Produced by organs and referred to other locations

• Diffuse and poorly located

• Accompanied by motor and autonomic reflexes (i.e. nausea and vomiting)

Neuropathic Pain

• Results from injury to neural structures within the peripheral and central nervous system

• Sharp, burning pain caused by aberrant somatosensory processing

Three types of neuropathic pain

• Peripherally-mediated (peripheral nerves and brachial plexus)

• Central pain syndrome (CNS)

• Sympathetically-mediated (central and peripheral)

Examples include post-herpetic neuralgia, diabetic neuropathy, central post-stroke pain, post-amputation pain

Idiopathic/Functional Pain

Pain resulting from an absence of neurologic deficit or peripheral abnormality.

Caused by changes in the nervous system emerging from:

• Genetic predisposition

• Anxiety or depression

• Increased psychosocial stressors

• Infections

• Trauma

Examples include fibromyalgia and tension-type headaches

Clinical Implications of Untreated Pain

Goals of Pain Management

Pain Assessment

Cornerstone to optimal pain management

Subjective approach (clinical assessment)

• Complete history & physical

• Medical, social, and psychiatric history

• Physical examination

• Laboratory and diagnostic tests (i.e. x-rays, MRI, etc.)

Objective approach (pain assessment tools)

• WILDA approach

• PQRST approach

The WILDA Approach to Pain Management

WILDA Assessment

Words:

The patient is asked to describe the pain in words, so that the doctor understands the nature of the pain, and can better address it. The following types of pain are differentiated in the WILDA guide:

• Neuropathic (nerve) pain, described as burning, shooting, radiating, tingling or electric

• Somatic (orthopedic) pain, described as aching, throbbing or dull

• Visceral (abdominal/bowel) pain, described as pressure, cramping or bloating

The medication administered to relieve pain depends on the patient’s description, and the pain’s known, or suspected, source.

Intensity:

Patients are asked to rate their pain on a scale from 0 to 10, with 0 representing a total absence of pain and 10 representing the worst pain possible. The scale is used to rate pain in the present, and after medication or other intervention. It helps the doctor to determine whether pain is improving, worsening or remaining at a constant level.

The Wong/Baker faces rating scale pairs each number on the pain scale with a facial expression. The scale is used for pediatric patients, elderly patients who are cognitively or verbally impaired, and patients who do not speak the language.

Location:

The majority of patients experience pain at two or more sites, so it is important for the clinician to be clear regarding which pain site the patient is describing.

Duration:

The duration of the pain over a period of time is significant. It is also important that the patient reports any flareups during a period of persistent pain.

Aggravating or Alleviating Factors:

The provider can discover a great deal about the source of pain from understanding factors that make the pain worse or better. Emotions, as well as physical acts or medications, may affect the intensity of pain.

In addition to medication, the following may be helpful in reducing pain:

• Music

• Relaxation or visualization techniques

• Massage

• Biofeedback

• Applications of heat or cold

• Injected corticosteroids

• Nerve-deadening agents

• Acupuncture

Factors that exacerbate pain include the following:

• Particular movements

• Exertion

• Cold or heat

• Blood draws

• Depression, fear, and anxiety

Factors that aggravate or alleviate pain are individualized and can vary for the same patient. Physical therapy or exercise can either improve the patient’s condition or worsen it, depending upon the specific circumstance.

The PQRST Approach to Pain Management

PQRST Pain Assessment Method

Since pain is subjective, self-report is considered the Gold Standard and most accurate measure of pain. The PQRST method of assessing pain is a valuable tool to accurately describe, assess and document a patient’s pain. The method also aids in the selection of appropriate pain medication and evaluating the response to treatment.

Providers can help patients more accurately report their pain by using these very specific PQRST assessment questions:

P = Provocation/Palliation

What were you doing when the pain started? What caused it? What makes it better or worse? What seems to trigger it? Stress? Position? Certain activities?

What relieves it? Medications, massage, heat/cold, changing position, being active, resting?

What aggravates it? Movement, bending, lying down, walking, standing?

Q = Quality/Quantity

What does it feel like? Use words to describe the pain such as sharp, dull, stabbing, burning, crushing, throbbing, nauseating, shooting, twisting, or stretching.

R = Region/Radiation

Where is the pain located? Does the pain radiate? Where? Does it feel like it travels/moves around? Did it start elsewhere and is now localized to one spot?

S = Severity Scale

How severe is the pain on a scale of 0 to 10, with zero being no pain and 10 being the worst pain ever? Does it interfere with activities? How bad is it at its worst? Does it force you to sit down, lie down, slow down? How long does an episode last?

T = Timing

When/at what time did the pain start? How long did it last? How often does it occur: hourly? daily? weekly? monthly? Is it sudden or gradual? What were you doing when you first experienced it? When do you usually experience it: daytime? night? early morning? Are you ever awakened by it? Does it lead to anything else? Is it accompanied by other signs and symptoms? Does it ever occur before, during or after meals? Does it occur seasonally?

Documentation

In addition to facilitating accurate pain assessment, careful and complete documentation demonstrates that you are taking all the proper steps to ensure that your patients receive the highest quality pain management. It is important to document the following:

Patient’s understanding of the pain scale. Describe the patient’s ability to assess pain level using the 0-10 pain scale.

Patient satisfaction with pain level with current treatment modality. Ask the patient what his or her pain level was prior to taking pain medication and after taking pain medication. If the patient’s pain level is not acceptable, what interventions were taken?

Timely re-assessment following any intervention and response to treatment.Quote the patient’s response.

Communication with the physician. Always report any change in condition.

Patient education provided and the patient’s response to learning. Don’t write “patient understands” without a supportive evaluation such as patient can verbalize, demonstrate, describe, etc.

Validated Pain Assessment Tools

The Pharmacist’s Role

• Utilizing multimodal analgesia to select an appropriate pain regimen

• Understanding the pharmacokinetic and pharmacodynamic properties of analgesics

• Managing adverse effects appropriately

• Recommending potential reversal agents for overdose

• Converting between opioid formulations

Multimodal Treatment Approach

• Use of more than one method or modality of controlling pain

• Nonpharmacologic and pharmacologic treatment

• Medications from two or more classes

To obtain additive beneficial effects, reduce adverse effects, or both

Clinical benefits of multimodal analgesia

• Earlier oral intake, ambulation, and hospital discharge

• Reduction in postoperative morbidity, mortality, and healthcare costs

A Stepwise Approach to Multimodal Analgesia

Adjuvant therapy: anticonvulsants (gabapentin, pregabalin), topical agents (lidocaine patch, capsaicin cream, diclofenac gel/cream), muscle relaxants (cyclobenzaprine, metaxalone, baclofen, methocarbamol, carisoprodol), antidepressants (SSRIs, SNRIs, TCAs)

Non-Pharmacologic Therapy

World Health Organization Analgesic Ladder

Non-Opioid Analgesics

Acetaminophen (APAP)

• MOA: inhibition of prostaglandin synthesis in the CNS

• Blocks peripheral pain impulse generation and increases pain threshold

• Lacks anti-inflammatory benefit; no effect on platelets

• Treats: Osteoarthritis, chronic lower back pain, migraine

• Harms and risks: Can be hepatotoxic at >3-4 grams/day and at lower dosages in patients with chronic alcohol use or liver disease

• Other considerations: May be less effective than treatment with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

 NSAIDs (i.e. ibuprofen, ketorolac, naproxen)

• MOA: inhibition of cyclooxygenase (COX) and inhibition of prostaglandin synthesis from arachidonic acid

• Reduces tissue inflammation and pain

• Treats: Localized osteoarthritis

• May cause gastrointestinal bleeding or perforation

• May increase renal risks with longer use or high dosage

• May increase risk of myocardial infarction or stroke with longer use or high dosage

• Other considerations: NSAIDs and COX-2 inhibitors are effective for acute and chronic low back pain without sciatica, but have more adverse effects than acetaminophen (Roelofs et al. 2008)

Adjuvant Therapy for Chronic Pain

Non-Opioid Analgesics

Select Anticonvulsants

• Examples: Pregabalin, gabapentin, and carbamazepine

• Treats: Neuropathic pain, including diabetic neuropathy, postherpetic neuralgia, or fibromyalgia

 Harms and risks:

• May cause sedation, dizziness, ataxia, or other side effects

• Other considerations: Select anticonvulsants may have abuse potential

Select Antidepressants

• Examples: Tricyclics (TCAs) and Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

• Treats: Neuropathic pain (diabetic neuropathy, postherpetic neuralgia, or fibromyalgia), migraine

 Harms and risks:

• TCAs are relatively contraindicated in severe cardiac disease, particularly in conduction disturbances

• TCAs have anticholinergic properties

 Other considerations:

• TCAs and SNRIs provide effective analgesia for neuropathic pain conditions including diabetic neuropathy and postherpetic neuralgia in patients with or without depression

• SNRIs are often better tolerated than TCAs

• Duloxetine is effective at reducing pain in diabetic peripheral neuropathy pain and fibromyalgia at 60 and 120 mg daily dosages (Lunn et al. 2014)

• Start TCAs at lower dosages, titrate as needed and as tolerated

• Some studies have demonstrated a moderate improvement in chronic low back pain with tricyclic or tetracyclic antidepressants (Staiger et al. 2011)

• Consider dosing TCAs at bedtime due to their sedating effects

Topical Agents

• Examples: Tricyclics (TCAs) and Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

• Examples: Lidocaine, Capsaicin, Topical NSAIDs

• Treats: Localized neuropathic pain, osteoarthritis, and other localized musculoskeletal pain

 Harms and risks:

• Initial flare or burning sensation

• Irritation of mucous membranes

 Other considerations:

• Can use topical agents as alternative first-line treatments

• Can be safer than systemic medications

• Some guidelines recommend topical NSAIDs for localized osteoarthritis pain over oral NSAIDs in patients over 75 years of age to minimize systemic effects and avoid systemic risks of oral NSAIDs

• Topical lidocaine can be used for localized neuropathic pain

• Topical capsaicin can be used for musculoskeletal and neuropathic pain

Interventional Approaches

• Examples: Epidural or intraarticular glucocorticoid injections, arthrocentesis

• Treats: Inflammatory arthritides such as rheumatoid arthritis, osteoarthritis, rotator cuff disease, some radiculopathies

Harms and risks:

• Epidural injections can be associated with rare but serious adverse events, including loss of vision, stroke, paralysis, and death

• Can also cause articular cartilage changes in osteoarthritis, joint infection, and sepsis

 Other considerations:

• Can improve short-term pain and function, but these benefits may not be sustained for long periods

• Removal of an effusion via arthrocentesis may be indicated prior to steroid injection

Opioid Analgesics

Mechanism of Action:

Opioids produce their actions at a cellular level by activating opioid receptors. These receptors are distributed throughout the central nervous system (CNS) with high concentrations in the nuclei of tractus solitarius, peri-aqueductal grey area (PAG), cerebral cortex, thalamus, and the substantia gelatinosa (SG) of the spinal cord. They have also been found on peripheral afferent nerve terminals and many other organs.  The efficacy of centrally applied opioids is well recognized, but when applied peripherally, for example in post-traumatic and inflammatory states, their actions are less reliable. Opioid receptors are coupled with inhibitory G-proteins and their activation has a number of actions including: closing of voltage sensitive calcium channels; stimulation of  potassium efflux leading to hyperpolarization and reduced cyclic adenosine  monophosphate  production. Overall, the effect is a reduction in neuronal cell excitability that in turn results in reduced transmission of nociceptive impulses.

Binds to opioid receptors in the CNS, peripheral nerve terminals, and GI tract

• Interact with mu (μ), delta (δ), or kappa (κ) opioid receptors

• Decrease release of excitatory neurotransmitters (i.e. glutamate)

• Decrease post-synaptic response to neurotransmitters

• Inhibition of ascending pain pathways, which alters response and perception of pain

Pharmacology of Opioids

• Opioid receptors coupled to G1 proteins

• Closure of N-type voltage-operated calcium channels

• Opening of calcium-dependent inwardly rectifying potassium channels

• Hyperpolarization and reduction in neuronal excitability

• cAMP results in decreased substance P

Opioid Receptor Effects

Classification of Opioids

Opioid Allergy vs. Pseudoallergy

9 out of 10 patients with a reported allergy to an opioid do not have a true allergy

– Codeine, morphine, and meperidine cause most allergic-type reactions

Symptoms resemble an allergic reaction but are actually a “pseudoallergic” reaction due to histamine release

– Itching, sneezing, flushing, sweating, asthma exacerbation

Symptoms of a true allergy

– Hives, maculopapular rash, erythema multiforme, pustular rash, severe hypotension, bronchospasm, angioedema

Cross-allergenicity

– Risk of cross-reactivity between opioids is thought to be less likely among agents from a different structural class

Initiation of alternative therapy

• Determine necessity for opioid agent

• Initiate NSAID or APAP around the clock if no contraindications exist

• If narcotic is required –

• Utilize lowest-possible dose (dose-dependent histamine release) OR

• Utilize high-potency opioid

• Administer antihistamine concurrently

Factors to Consider When Selecting An Opioid

Opioid Drug Therapies

Morphine

• Significant histamine-release reactions (i.e. itching)

• Active metabolite may accumulate in renal failure

• Prolonged sedation

• Available as immediate-release and sustained-release oral formulations

Hydromorphone

• 7 times more potent than morphine

• No formation of active metabolites

• Good choice for patients with tolerance to morphine or patients experiencing histamine-release reactions

Fentanyl

• 100 times more potent than morphine

• Least amount of histamine-release reactions

• No formation of active metabolites

• Drug of choice for hemodynamically unstable, mechanically ventilated patients

• Short duration of effect often requires a continuous infusion

• Available as a long-acting patch, buccal tablet, and immediate-release dosage forms

Codeine

• Weak analgesic (often co-formulated with acetaminophen)

• Prodrug metabolized by CYP2D6 to active metabolites

• 10% of US population are unable to convert codeine to the active metabolite

Oxycodone

• Available as immediate-release and extended-release oral formulations

• Immediate-release formulation onset of action is 10-15 minutes (may take up to 80 minutes for maximum effect)
  

• 5 mg oxycodone = 40 mg codeine

Meperidine

• Not routinely used for analgesia (active metabolite may accumulate and lead to seizures)

• Significant histamine-release reactions

• Several doses may be given for post-operative rigors

Methadone

• Strong opioid agonist and n-methyl-D-aspartate (NMDA) antagonist

• Analgesic effects last 6-8 hours

• Long terminal half-life (approximately 27 hours)

• QTc prolongation (interaction with quinolones, macrolides, antipsychotics, and amiodarone)

Tramadol

• Synthetic analogue of codeine
  

• Binds to mu receptors and inhibits norepinephrine and serotonin reuptake

• Active metabolite that is 6 times more potent

• May have increased risk of seizures with concomitant MAOI, SSRI, TCA, or opioid administration

Tapentadol

• Weak opioid agonist
  

• Serotonin and norepinephrine reuptake inhibitor

• Effective option for patients with GI effects from other opioids

• Also approved for diabetic peripheral neuropathy

Pharmacokinetic Properties of Opioids

• Majority of opioids are metabolized through phase I metabolism via CYP450 enzymes 2D6 and 3A4

Hepatic impairment and cirrhosis

• Gastritis – delayed drug absorption

• Ascites -increased volume of distribution – increased adverse effects of hydrophilic opioids (i.e. morphine, oxycodone)

• Decreased production of alpha-1-acid glycoprotein and albumin

• Increased free drug levels of highly protein-bound opioids (i.e. methadone and buprenorphine)

Start Low and Titrate Slow!

Dosing Recommendations in Hepatic Impairment

Pharmacokinetic Properties of Opioids

 Renal impairment

• Approximately 1/3 of patients with a CrCl < 50 mL/min are administered an opioid for pain
  
  
  Opioid-Related Adverse Effects
  
  Sedation
  

• Results from anticholinergic activity of opioids

• More common when initiating therapy or when increasing dose

• Resolves within days to weeks

• Opioid rotation and dose reduction if possible

• Psychosomatic simulants (i.e. methylphenidate)
  
  Nausea and Vomiting
  

• Results from direct stimulation of chemoreceptor trigger zone

• Results within several days

• Initiation of antiemetic agents (ondansetron, metoclopramide, prochlorperazine, etc.)

Constipation

• Occurs in 40-95% of all patients treated with opioids

• Results from mu receptor activation in the gastrointestinal tract, leading to decreased gut motility

• Unlikely to improve over time

Long-term consequences

• Significant morbidity and mortality

• Decreased quality of life

Aggressive prophylaxis

• Stimulant laxative (i.e. senna or bisacodyl) and a stool softener (i.e. docusate) scheduled around the clock
  
  Cardiac effects
  

• Not very common

• Morphine-associated histamine-release and subsequent vasodilation and hypotension

• QTc prolongation resulting from parasympathetic stimulation and bradycardia

• Effects are completely reversed with naloxone administration

Bladder dysfunction

• Results from inhibition of the voiding reflex

• More common with postoperative patients

• Effects are reversible with naloxone
  
  Histamine-release reactions
  

• Associated with lower potency opioids (i.e. morphine)

• Flushing, tachycardia, hypotension, and pruritis

• Utilize lower doses of opioids or switch to a more potent agent (i.e. hydromorphone)

• If opioid is required, administer an antihistamine

Opioid Addiction

Addiction: complex disease involving physiological, psychological, and social aspects

Pseudo-addiction: aberrant behavior in patients not truly addicted to opioids

Ex. Once patient receives adequate analgesia, the drug-seeking behaviors cease

Fear of inducing a new addiction with appropriate opioid use should NOT be a barrier to providing adequate pain relief.

Tolerance: constant opioid dose provides a decreased effect

• Opioid-related adverse effects will develop over several days to weeks (except for constipation)

• More frequent administration of analgesia over time
  
  Physical dependence: predictable pharmacologic effect
  

• Withdrawal symptoms after abrupt discontinuation of therapy

• Commonly occurs after 2 weeks of therapy

• Symptoms include drug craving, nausea, abdominal cramps, muscle aches

• Nonverbal patients may appear restless, irritable, dysphoric, anxious, delirious, or have increased pain sensitivity

Opioid Overdose

Preventable and potentially lethal condition resulting from:

• Prescribing practices

• Inadequate understanding on risk of opioid misuse

• Drug administration errors

• Pharmaceutical abuse
  
  Clinical implications:
  

• Life-threatening toxic effects in multiple organ systems

• Pharmacokinetic changes leading to prolonged complications

• Inappropriate treatment decisions

Naloxone: The Antidote for Opioid Overdose

MOA: competitive μ opioid-receptor antagonist

Routes of administration:

Parenteral

• Intranasal

• Pulmonary

• Oral route (negligible bioavailability)

 Onset of action: < 2 minutes (IV)

Duration of action: 20 to 90 minutes

Dosing:

• Initial: 0.04 mg

• Increase every 2 minutes, if no response

• Maximum dose: 15 mg

Naltrexone: The Antidote for Opioid Overdose

MOA: potent, long-acting, pure opiate antagonist

Route of administration: oral

Duration of action: up to 72 hours

Recommended dosing:

• Day 1: 25 mg

• If no withdrawal signs occur, may increase to 50-300 mg/day

Equianalgesia

Analgesic and sedative effects of opioids are similar when administered in equipotent doses

Example: hydromorphone 1 mg = morphine 7 mg

Special considerations:

Equianalgesic Dosing

Converting Between Opioids

Steps to convert between opioids:

• Determine the total 24-hour opioid requirement of current medication

• Set up equianalgesic equation:
  
  

• Solve for X

• Reduce dose by 25-50% to account for incomplete cross-tolerance

• Divide the total calculated dose by the frequency

Opioid Conversion Example

A 50-year old female admitted to the hospital due to progressively worsening back pain. Patient takes 2 tablets of oxycodone-acetaminophen 5/325 mg every 4 hours, with no relief. The physician wants to start the patient on oral hydromorphone and asks you for a dose recommendation.

Step 1: Determine the 24-hour opioid requirement for the current medication.

2 tablets oxycodone-acetaminophen 5/325 mg Q4H = 60 mg oxycodone in 24 hours

Step 2: Set up the equianalgesic equation.

Step 3: Solve for x.

X = 22.5 mg PO hydromorphone in 24 hours

Step 4: Reduce dose by 25-50% to account for incomplete cross-tolerance.

22.5 mg PO hydromorphone x 0.25 = 5.625 mg PO hydromorphone

22.5 mg PO hydromorphone – 5.625 mg PO hydromorphone = 16.88 mg PO

hydromorphone in 24 hours

Step 5: Divide total calculated dose by frequency (divide by 6 for Q4H dosing)

16.88 mg PO hydromorphone/6 = 2.8 mg PO hydromorphone every 4 hours ≈ 2 mg PO Q4H

Role of Pharmacy Professionals

Community pharmacists can play a role in pain management by collaborating with local physicians, nurses, nurse practitioners, and physician assistants. Establishing open lines of communication with these health care providers helps to ensure the safety of mutual patients regarding controlled substance medications. In addition to informing providers about drug interactions, dosing concerns, or possible misuse of prescriptions, pharmacists can help local prescribers to stay up to date on new updates of therapy or new laws and policies concerning controlled substance prescriptions such as the expansion of naloxone distribution. A good working relationship with local providers will also help to ensure better reception of recommendations. The next few sections describe a few of the issues that are ripe for pharmacist-prescriber collaboration.

High Risk Medications

All opioid medications should be considered “high risk” from the aspect of dispensing due to the potential for harm including abuse, misuse, and overdose. In addition to specific opioids, other pain medications have been identified by the American Geriatric Society (AGS) as high-risk medications to be avoided in the elderly. The AGS publishes the Beers Criteria to identify medications with a high probability of adverse events in the elderly using a systematic review. Of the medications identified by the AGS Beers Criteria, a portion are incorporated into the list maintained by the National Committee for Quality Assurance (NCQA) which is the reference for the “High Risk Medication” measure that is once again set to be part of the Medicare Part D Star Rating System in the 2016 plan year. Pharmacists can have an impact on preventing initiation or encouraging discontinuation of high-risk medications by regularly screening new prescriptions, and by completing medication therapy management (MTM) cases assigned by OutcomesMTM and Mirixa. While performing this service, pharmacists can consult both patients and physicians to find the best alternative therapy for pain management in older adults without causing unwanted and potentially dangerous adverse effects. Reducing the use of high-risk medications in the elderly will not only help patients but will also help the pharmacy have an objective metric that it is providing high quality care.

Safe Storage and Disposal

News headlines and reports of disciplinary action from state boards taken against licensed health care professionals document the persistent demand for diverted controlled substances. Diversion by doctors and other prescribers, nurses, pharmacists, pharmacy and medical technicians, home health workers, family members, and visitors happens when medications are stolen or illegally sold from hospitals, pharmacies, or patients. As theft continues to be a threat to adequate pain management, safe storage is an important part of patient education when initiating opioid therapy. Counseling tips for patients new to opioid therapy include not sharing their medical information with friends and family to prevent being targeted, maintaining an inventory of medication to detect theft, and only carrying a small amount of medication when traveling.

Patients should regularly clean out their medication cabinet to dispose of medications no longer needed. The Drug Enforcement Administration (DEA) has finalized rules governing the disposal of controlled substances by its registrants and consumers. These regulations permit authorized manufacturers, distributors, reverse distributors, and retail pharmacies to voluntarily administer mail-back programs and maintain collection receptacles. In addition, the finalized rule expands the authority of authorized hospitals/ clinics and retail pharmacies to voluntarily maintain collection receptacles at long-term care facilities. Some state laws prohibit the establishment of such collection sites when not located in a law enforcement center.

In July 2015, the DEA announced the Take Back Days would resume in September 2015, although the press release did not mention a reason for reinstating the program. The FDA offers instructions for certain medications (basically anything containing an opioid analgesic) to be flushed once no longer needed and proper disposal in household trash when authorized collection sites are not available. The FDA-recommended disposal methods include removing the label or blackening out personal information, emptying the medication into a sealable container and mixing with an undesirable substance such as kitty litter, used coffee grounds, or dirt. Pharmacists can provide education to patients in need of disposing unwanted medications, both controlled and non-controlled substances. It is important that patients are aware of how to safely dispose of medications as it can be a hazard to other family members, especially children and pets. Several options available for pharmacies to offer to patients for home use include pre-paid mail away packages or home deactivation kits. In addition to home disposal options,

pharmacies may now explore reverse distributor options when allowable by their state and local regulations to collect and dispose of returned medications. By providing a safe way to dispose of these medications, pharmacists can prevent an accidental overdoses.

Preventing Diversion

Opioid use disorders are broken down into three categories: misuse of prescribed opioid medications, use of diverted opioid medications, and use of illicitly obtained heroin. As patients with legitimate diagnoses warranting opioid therapy are not immune from opioid use disorders, caution should be used with all opioid prescriptions to ensure safe and proper use by the patient.

When speaking of prescription diversion, many pharmacists think of altered or forged prescriptions. One of the quickest ways to alter a prescription is the addition of a digit to the quantity or strength to change the dispensed quantity or strength to a higher amount. Pharmacists and pharmacy technicians can identify this red flag in prescriptions altered in this fashion by comparing the quantity prescribed to the directions and prescriber’s specialty.

For example, a prescription written by an emergency department provider for an opioid four times a day seems more logical to be written for a quantity of 20 for a five-day supply as opposed to a quantity of 120 for a 30-day supply.

Additional evidence of an altered prescription include signs of rinsing or removing previous ink by rinsing the prescription with acetone or xylene, such as the use of different ink on different parts of the prescription, or a “water” line on the prescription where the rinsing occurred.

An important tool for prescribers and pharmacies to use against unauthorized changes to a written prescription is e-prescribing. It ensures that no one other than the prescriber or pharmacy has access to the prescription to copy or alter it. E-prescribing of controlled substances is permitted in all 50 states and as of August 2015, every state permit prescriptions for Schedule II-V drugs to be sent electronically. Pharmacy vendors report that they have met security requirements to receive e-prescriptions for controlled substances and the upcoming deadline in New York state to send all prescriptions electronically is putting pressure on prescriber software vendors.

Regulators and lawyers are taking a greater interest in the extent to which pharmacists and prescribers may be liable for misused and diverted prescription drugs. The Code of Federal Regulations, Title 21, section 1306.04 states: “a prescription for a controlled substance must be issued for a legitimate medical purpose by an individual practitioner in the usual course of their professional practice, and the pharmacist possesses a corresponding responsibility to ensure the prescription is used legitimately.” A violation of this section is no longer based on the pharmacist knowing it is not for legitimate medical

practice, but should have known.

More recently, the state Supreme Court of West Virginia ruled patients addicted to controlled substances could file lawsuits against the prescribers and pharmacists who contributed to their addiction. The plaintiffs in the eight lawsuits against the four physicians and three pharmacies claimed their addiction resulted in their criminal abuse of and criminal activity to obtain the controlled substances. This ruling provides the strongest highlight of the responsibility to dispense the prescribed medication correctly only after analyzing the drug therapy for safe, effective and appropriate use.

As the pharmacist’s duty to determine the medical legitimacy of prescriptions is put in the spotlight, what are the warning signs or red flags of illegitimate medical use?

In an effort to help educate pharmacists to identify warning signs of diversion and abuse, the National Association of Boards of Pharmacy (NABP) and Anti-Diversion Industry Working Group (ADIWG) have released a video titled “Red Flags” and is available to view in the pharmacist’s section of NABP’s AwareRx.com prescription safety website (www.awarerx.org/pharmacists).

Red flags of prescription drug abuse include groups of patients presenting with similar prescriptions from the same office, prescriptions from distant locations, high dose or ongoing pain medications from a provider not specialized in pain, using street slang for medication names, requesting early refills, or willingness to pay cash for opioids despite prescription insurance coverage. Additional warning signs include prescriptions for drug cocktails of an opioid + a benzodiazepine + a muscle relaxant, which are used together to intensify the effect of the medications. Hydrocodone, alprazolam, and carisoprodol are known as the “trio” or “trinity”; when oxycodone is included with alprazolam and carisoprodol, it is described as the “holy trinity.”

Doctor shopping or pharmacy shopping is another red flag for prescription misuse and diversion. When claims for identical or similar medications are adjudicated to prescription insurance, the insurance may reject the claim for refill too soon. Detecting multiple prescriptions for similar medications filled at multiple pharmacies becomes more difficult as patients become more sophisticated and track their refill dates, request similar but not identical prescriptions, or pay cash to prevent insurance rejections. Pharmacists who have access to a prescription drug monitoring program (PDMP) to monitor patient activity at other pharmacies should utilize it. If it is discovered a patient is using multiple pharmacies to fill narcotic prescriptions, an open dialogue with the patient is necessary to determine the reasoning for using multiple pharmacies. Similarly, if the patient is using several prescribers to receive controlled substances, pharmacists should make the prescribers aware of the situation. It should be stressed to patients to use one pharmacy, or one pharmacy chain with networked dispensing records, to decrease the likelihood of missed drug interactions, duplications in therapy or other dangerous prescription cocktails.

Prescription Drug Monitoring Program

Each state, except for Missouri, has established a PDMP to collect prescription dispensing data from pharmacies at regular intervals every 7-30 days. Each individual PDMP determines what drug schedules are reported from only schedule II to schedule II-V. Information sent to the program includes patient name and date of birth, medication name and strength, quantity, day supply, prescriber, and dispensing pharmacy. Pharmacists, prescribers, and law enforcement agencies may request access to the program to perform a patient search. Because all information is provided to the program, regardless of payment method, patients are no longer able to “beat the system” by receiving prescriptions from different prescribers, filling at different pharmacies, and paying cash to avoid any insurance flags.

Dozens of studies have reviewed the use of the PDMP programs to determine their efficacy in reducing medication diversion, and a complete review of evidence is available on the PDMP Center of Excellence Briefing of PDMP Excellence. Highlights of the report include:

• In Ohio emergency departments, 41 percent of medical providers altered their prescribing for patients receiving multiple narcotics at the same time. Of the 41 percent, 61 percent prescribed no narcotics or fewer than anticipated.

• In California, 74 percent of physicians who responded to the survey indicated they had altered their prescribing practices as a result of using the PDMP.

• Doctor shopping in Florida decreased 51 percent after the creation of the PDMP.

However, not all PDMP systems are connected, so patients may visit multiple providers and multiple pharmacies in neighboring states without being flagged to a pharmacist when dispensing. Within the United States, 29 PDMPs are actively sharing data and four others are in the process of establishing data sharing, connected states are listed on NABP’s PMP InterConnect webpage (www.nabp.net/programs/pmp-interconnect/nabp-pmp-interconnect). Until all systems are connected and actively sharing data, pharmacists should consider registering for PDMP programs in nearby bordering states and verifying patient activity with each system prior to dispensing.

Pain Contracts

Pain contracts (also described as opioid contracts or opioid treatment agreements) are agreements entered into by the patient and provider when entering a pain management program. The contracts serve several purposes: providing the patient with information about the risks of opioid therapies, outlining monitoring procedures to ensure proper opioid use, restricting the obtaining of opioids from multiple providers, and allowing for more complete management of the patient’s pain. Aspects of pain contracts may include provisions for monitoring such as medication counts, urine drug screens, and scheduled office visits to detect improper medication usage, including overuse and diversion. The contract may also require the use of one pharmacy to assist in the monitoring for opioids from one provider. Pharmacists should be aware of the multitude of non-controlled medications that can result in a positive urine drug screen, such as quetiapine, diphenhydramine, and ibuprofen. The false positives occur due to the similar shape between these medications and the shape of the opioid the urine screen is detecting.

Pain contracts may be perceived by some patients as a lack of trust or limitations preventing adequate pain control. These negative perceptions should be discussed with the patient with the goal by all parties to optimize pain management in a safe manner. While the many stipulations in pain contracts can seem restrictive to the patient’s autonomy, a systematic review of four observational studies found a modest decrease of 7-23 percent in opioid misuse when a pain contract was implemented, compared to a control group with no contract.

Motivational Interviewing

Pharmacists are uniquely positioned to provide counseling for pain management expectations and the patient’s goals of therapy at the point of dispensing each month. During the patient encounter, patient autonomy should be emphasized, and the patients should be included in their decision making. A pharmacist may place the focus of pain management on patients discussing their goals of therapy, concerns about cost or adverse effects or relief experienced with current regimen to place patients in control of their own treatment. Motivational interviewing is based on three key elements for success: collaboration with the patient, evoking or drawing out the patient’s ideas about change, and emphasizing the patient’s autonomy and decision-making power in health care decisions. When interviewing patients, asking questions regarding how they feel about a particular treatment option, or requesting permission to contact their prescriber for changes to therapy allow patients to believe they are an active part of their treatment plan.

“Change talk” are statements made by patients revealing consideration of, motivation for, or commitment to change, and should be a factor considered in driving pain management therapy. With change talk, pharmacists can gain a better understanding of how likely a patient is to follow through with changes using several types of questions to elicit six different types of change talk. The different types of change talk include statements about a desire for change, capability for change, reasons for change, feeling obliged to change, commitment to change or actions taken. The first four provide insight on the desire to commit change, or precommitment to change, but no action to change behaviors. The last two are the action phase of change and should be the ultimate goal of discussing change talk.

Using the patient’s own desires and motivation for change can assist in the development of SMART (specific, measurable, attainable, realistic and timely) goals to convert precommitment talk to action. These goals can be related to several aspects of pain management: incorporation of non-pharmacologic options into therapeutic plan, decrease in use of as needed medication to decrease adverse effects, or other goals important to the patient. Pharmacists can use the patient-developed SMART goals to help track improvement in the control of pain and decrease reliance on pain medications to perform daily activities.

As pharmacists are the last line of defense before a medication reaches a patient, it is critical that pharmacists remain updated on the current trends of pain medication use and misuse. It is the pharmacist’s responsibility to ensure that patients are receiving safe and effective dosages of pain medications to avoid accidental overdoses. Each prescription should be carefully analyzed for potential dangers, even if it is the same dosing as previous prescriptions. Factors to consider when reviewing the prescription include adverse events, development of tolerance, inadequate pain relief, and misuse of medication. When filling prescriptions, technicians and pharmacists should pay close attention to early refills and start a dialogue with patients if they are requesting early refills frequently, as this may be a sign of inadequate pain relief, misuse, or abuse. In either case, patients should be counseled on the importance of following the prescriber’s directions, the dangers of not taking their medication as prescribed, and to speak to their prescriber about changing their regimen if their pain is not currently controlled.

Common adverse effects pharmacists should screen for at each dispensing include constipation, dizziness, and falls. This is especially important in the elderly population, as older adults are more susceptible to experiencing adverse effects and could develop new adverse effects while on a stable regimen due to changes in renal or hepatic function. If patients are experiencing adverse effects, pharmacists should make appropriate recommendations for both nonpharmacologic and pharmacologic therapy. Educating patients on what is considered a true drug allergy should be included in counseling regarding adverse effects.

Conclusion

Pain is a complex condition that requires careful and continuous assessment. Multimodal analgesia should be used if possible, to minimize adverse effects and the potential for abuse. Pharmacists play a crucial role in opioid education, equianalgesic dosing and optimization of analgesia.

Overall, by taking an active role in pain management, community pharmacists can help patients to receive adequate pain control while eliminating undesirable and potentially dangerous side effects. By educating patients on side effects, proper medication disposal, and proper usage of pain medications, along with working with local physicians, pharmacists can be a great benefit in the practice of pain management.

Active Learning

Gaps in the Pharmacist’s Pain Management Role. A study provides insight into pharmacists’ perceptions of pain practice and the realities of dispensing scheduled pain medications.

https://www.practicalpainmanagement.com/resources/practice-management/gaps-pharmacist-pain-management-role 

Pain Management Best Practices inter-agency Task Force Report. Updates, Gaps, Inconsistencies, And Recommendations.

https://www.hhs.gov/sites/default/files/pmtf-final-report-2019-05-23.pdf

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