continuing education

Innovations in Pain Management: New Drug

Developments, Targets, and Strategies for
Safe and Effective Analgesia
By Michele Matthews, PharmD

U pon successful completion of this

continuing education activity, the
pharmacist should be able to:
1. Describe the socioeconomicburden
of pain and identify issues with cur-
rent analgesic therapies.
2. Discuss new drug developments for pain man-
agement and provide education to patients
who are prescribed these therapies.
pain secondary to low back
pain, arthritis, or headache.
The cost of chronic pain is
staggering, resulting in more
than $100 billion each year
from the combination of
work absenteeism along with
direct medical costs. There-
fore, proper pain assessment
Useful Websites

■ www.aspi.wisc.edu/
This is the website of the Alliance of State
Pain Initiatives (ASPI). Formerly known as
the American Alliance of Cancer Pain Ini-
tiatives (AACPI), this is a network of state-
based organizations that work through
education, advocacy, and institutional
improvements to remove the barriers that
3. Describe the abuse-deterrent and tamper- and management is becom-
impede pain relief.
resistant strategies for the new formulations of ing an important health issue
■ www.painfoundation.org
opioid analgesics. with forthcoming changes in
This is the website of the American
4. Identify novel drug targets for pain manage- the health care system and
Pain Foundation (APF), an independent
ment, including the role of the endocannibinoid realization of the actual risks nonprofit organization serving people
system. to the patient associated with with pain through information, advocacy,
5. Discuss the role of pharmacogenomics that some analgesics. and support.
may assist with choosing personalized medi- Pain is categorized
cine for patients with pain. based on factors including severity, duration, and quality.
Pain can be classified as acute (lasting less than one month)
Introduction or chronic (lasting greater than six months) and can arise
According to the International Association for from nociceptive and/or neuropathic origins. Nociceptive
the Study of Pain, pain is defined as an unpleas- pain is experienced in the presence of an injury or trauma
ant sensory and emotional experience associ- and can be described using terms such as sharp, dull, or
ated with actual or potential tissue damage, or achy. This type of pain can be localized or diffuse; examples
described in terms of such damage. However, of nociceptive pain include osteoarthritis and pancreatitis.
any standardized definition does not fully ap- Neuropathic pain, defined as pain initiated or caused by a le-
preciate the subjective nature of pain and its sion or dysfunction within the nervous system, is commonly
associated physical, emotional, and behavioral described as one or more of the following: burning, shoot-
elements. The impact of pain is far-reaching; ing, or electrical shock-like pain that may not be easily local-
pain affects more Americans than heart disease, izable to a single point. Diabetic peripheral neuropathy and
diabetes, and cancer combined, with an esti- postherpetic neuralgia are classic examples of neuropathic
mated 80 million people suffering from pain in pain. A detailed patient history and pain assessment are the
the United States each year. Approximately 68 guiding factors in choosing appropriate analgesic therapies
million of these cases are classified as chronic for both acute and chronic pain, regardless of severity.

www.americaspharmacist.net January 2011 | america’s Pharmacist 55

 The pharmacology of pain management involves the for dependency or abuse associated with opioid
modulation of the ascending and descending pathways analgesics have also lead to opioid product
within the pain process along with inhibition of the release formulations that may deter abuse and resist
of excitatory neurotransmitters and/or other substances tampering. In tandem, the Food and Drug Ad-
that sensitize the nervous system to noxious stimuli. When ministration (FDA) has developed a long-acting
the body experiences an injury or trauma, action potentials and extended-release opioid class Risk Evalua-
are generated from the site of damage and are transmitted tion and Mitigation Strategies (REMS) to further
from the peripheral nervous system to the central nervous address such risks. This article will review new
system (CNS) via the spinal cord. Simultaneously, chemi- drugs, formulations, and strategies to address
cal mediators and neurotransmitters that sensitize neurons the challenges in pain management and will
and enhance the pain process are released. Once the pain highlight the evolving science behind achieving
impulses have reached the higher centers of the CNS, a effective analgesia.
modulatory response is initiated within the descending
pathway to inhibit pain impulses from being processed and New Drugs or Formulations
ultimately preventing pain perception. The receptors in- Nonopioid and Adjuvant Analgesics
volved in pain modulation include opioid receptors, alpha-2 Intravenous Ibuprofen (Caldolor)
adrenergic receptors, voltage-gated calcium channels, and Nonsteroidal anti-inflammatory drugs have been
NMDA receptors. Chemical mediators that sensitize neu- utilized for acute pain management, fever, and
rons to pain include substance P, prostaglandins, brady- inflammation since aspirin was discovered in the
kinin, and glutamate. Neurotransmitters that facilitate pain 1800s. The approval of COX-2 inhibitors for use in
modulation include norepinephrine, serotonin, and GABA. the U.S. market in 1999 with celecoxib provided
The various processes involved in pain perception al- optimism for retaining the analgesic efficacy as-
lows for the targeting of different areas within the pain path- sociated with nonselective NSAIDs, while avoiding
way with the use of pharmacological agents. Drugs used to gastrointestinal and renal toxicity. The subsequent
treat pain are categorized as nonopioid, opioid, and adju- withdrawal of multiple COX-2 inhibitors from
vant analgesics. Nonopioid analgesics include acetamino- the market due to cardiovascular events led to
phen and non-steroidal anti-inflammatory drugs (NSAIDs) widespread re-evaluation of the risks associated
and are commonly prescribed as monotherapy for mild to with both selective and nonselective NSAIDs. A
moderate pain or in combination with opioids for moder- scientific statement from the American Heart As-
ate to severe pain. Opioids analgesics are the mainstay of sociation established criteria to delineate patients
therapy for moderately severe to severe pain and are used at risk for NSAID-induced cardiovascular events
in combination with nonopioid and adjuvant analgesics and highlighted the need for improved drug safety
in the setting of chronic pain. They are involved in CNS- regulations. Even though these agents play a
mediated mechanism of analgesia through their interaction significant role in pain management, the devel-
with opioid receptors in the brain and spinal cord. Adjuvant opment of new NSAIDs or formulations may be
analgesics, including antidepressants and anticonvulsants, received with caution. Consequently, the approval
can be used for any severity of chronic pain in combination of intravenous (IV) ibuprofen (Caldolor) revisits the
with nonopioid and/or opioid analgesics. role of parenteral NSAIDs after years of experience
The current arsenal in the management of both acute with ketorolac tromethamine.
and chronic pain is limited. Even with several therapeu- Approved by the FDA in June 2009, IV
tic options available, there remains a need for innovative ibuprofen is indicated for the management of
therapies based on the individualistic response to analge- mild to moderate acute pain, moderate to severe
sics and the ever-growing understanding of pain and its acute pain as an adjunct to opioid analgesics,
processing. Additionally, the pharmacogenomics of pain and reduction of fever in adults. In a multicenter,
are becoming increasingly understood and may explain randomized, double-blind, placebo-controlled
these differences in patient response to therapy. The risk trial, 406 patients who were undergoing elective

56 america’s Pharmacist | January 2011 www.americaspharmacist.net

orthopedic or abdominal surgeries were random- should be well hydrated and have no history of hypersen-
ized to IV ibuprofen 400 mg, IV ibuprofen 800 sitivity to ibuprofen, other NSAIDs or aspirin. IV Ibuprofen is
mg, or placebo every six hours in combination contraindicated in the coronary-artery bypass graft (CABG)
with morphine via patient-controlled analgesia post-operative setting. The cost of IV ibuprofen will also likely
(PCA) pumps for the management of postopera- play a significant role in formulary decision-making ($9.19 for
tive pain. Twenty-four hours after surgery, patients 400 mg, $13.13 for 800 mg; per dose).
in the IV ibuprofen 800 mg required significantly
less morphine compared to the placebo group Milnacipran (Savella)
(P=0.030). The most common treatment-emer- An improved understanding of pain processing has led to
gent adverse effects were nausea, vomiting, and focusing on the modulation of neurotransmitters that as-
constipation, all of which occurred at a much sist with preventing pain perception. Norepinephrine (NE)
lower rate compared to the placebo group. A reuptake inhibition within the descending pain pathway
multi-center, randomized, double-blind, placebo- of the central nervous system (CNS) has been proposed
controlled trial evaluated the efficacy and safety to suppress pain impulse transmission that is likely to be
of IV ibuprofen for the treatment of fever from dependent upon patient-specific plasticity. Serotonin and
any cause. One hundred twenty patients were NE reuptake inhibitors (SNRIs) such as duloxetine are
randomized to IV ibuprofen 100 mg, 200 mg, beneficial for the treatment of both pain and associated
400 mg, or placebo administered every four depression. However, serotonin (5-HT) has been pro-
hours for a total of six doses. After four hours of posed to increase inflammation and hyperalgesia (such
therapy, the proportion of patients achieving a as exaggerated pain response), particularly in the pres-
temperature of 101°F or lower was 61 percent for ence of nerve injury. Milnacipran (Savella) selectively in-
IV ibuprofen 100 mg (P=0.0264), 70 percent for hibits NE and 5-HT reuptake in a 3:1 ratio and is approved
200 mg (P=0.0043), and 77 percent for 400 mg for the management of fibromyalgia. It is theorized that
(P=0.0005) compared to 32 percent in the pla- this specificity for NE over 5-HT may provide enhanced
cebo group. This study also evaluated the effects analgesia while minimizing adverse effects including
of IV ibuprofen in critically ill versus non-critically 5-HT syndrome and hyperalgesia. Milnacipran has been
ill patients and found that non-critically ill patients studied in more than 2,000 patients with fibromyalgia, and
experienced a slightly more rapid reduction in when compared to placebo for up to 27 weeks, its use
temperature after administration of a 400 mg was associated with greater improvements in a composite
dose. In addition, the 400 mg dose was effective endpoint that included pain, physical function, and patient
in both lowering and maintaining temperatures to global assessment. Milnacipran requires titration through-
normothermic range over the 24-hour period. The out the first week of therapy to a final recommended dose
incidence of adverse effects was similar between of 50 mg by mouth twice daily. To facilitate titration, it is
all groups, with the exception of bacteremia with supplied as a blister-pack for the first four weeks of ther-
IV ibuprofen 100 mg (13%; n=4) compared to 0 apy. Milnacipran carries a black box warning for suicidal
percent placebo (0%; P=0.045). ideation, thinking and behavior in children, adolescents
The evidence regarding the use of IV ibupro- and young adults. The most common adverse effects
fen for acute pain suggests that it can be used as associated with milnacipran include nausea, headache,
an alternative to other analgesics or adjunctively to palpitations, and dry mouth, and it should be used cau-
reduce opioid requirements in the postoperative tiously in patients on other serotonergic drugs or those
setting. To date, there are no studies comparing with seizure disorders; concomitant use with a MAOI is
the efficacy and safety of IV ibuprofen to ketoro- contraindicated. Discontinuation of milnacipran should be
lac. Additionally, the use of IV ibuprofen has been done gradually when possible to avoid withdrawal symp-
limited to five days in clinical trials and is the same toms. Comparative efficacy studies involving milnacipran
duration of therapy restriction that applies to the and other drugs for the treatment of fibromyalgia (such as
use of ketorolac. Patients receiving IV ibuprofen duloxetine, pregabalin) are unavailable.

www.americaspharmacist.net January 2011 | america’s Pharmacist 57

Opioid Analgesics if the tablet is broken, chewed, crushed or dis-
Extended-release Hydromorphone (Exalgo) solved and can lead to a potentially fatal dose of
Hydromorphone is a hydrogenated, semi-synthetic ketone hydromorphone. Exalgo should not be used with
of morphine that is used in the management of moderate or within 14 days of discontinuing MAOI therapy.
to severe pain. As a derivative of morphine, it is expected
that hydromorphone is an effective alternative to morphine. Fentanyl Buccal Film (Onsolis)
Hydromorphone is available as an oral formulation, but The lipophilic nature of fentanyl has allowed it to
the short elimination half-life of this drug requires frequent be developed into multiple formulations for ad-
repeated dosing (every four to six hours) to gain effective ministration through various routes. Fentanyl buc-
around-the-clock pain control. The need for frequent dosing cal soluble film (FBSF, Onsolis) is FDA-approved
may lead to issues with adherence and consequently may for the treatment of breakthrough pain in patients
reduce treatment outcomes and may negatively impact qual- with cancer, age 18 and older, who are managed
ity of life. Studies have shown that long-acting opioids can on long-acting opioid therapy. It utilizes BioErod-
improve pain management and reduce opioid-related side ible MucoAdheresive (BEMA) technology and
effects in comparison to immediate-release (IR) formulations. dissolves within 15 to 30 minutes. In a random-
Exalgo is indicated for once daily administration for the ized, double-blind, placebo-controlled trial, 80
management of moderate to severe pain in opioid toler- opioid-tolerant patients with chronic cancer pain
ant patients. This long-acting formulation provides lower were randomized to FBSF or placebo. After 30
and longer sustained peaks than IR hydromorphone, as minutes, significantly more patients in the FBSF
well as higher trough concentrations. This pharmacokinetic group reported greater reductions in pain com-
profile provides an easier dosing schedule, shows potential pared to placebo; this improvement in pain was
to lower medication abuse, and can eliminate the wearing detectable within 15 minutes after administration
off effect caused by low trough drug levels that may ex- and was sustained for up to one hour. The most
ist in patients using IR hydromorphone. Extended-release common adverse effects associated with FBSF
hydromorphone provides another option for patients with include nausea, vomiting, and constipation and
chronic cancer or noncancer pain who require long-acting carries the same risks for respiratory depression,
opioid formulations. By reducing the number of pills needed hypotension, and addiction as with other opioid
on a daily basis, health care providers can improve patient analgesics. The recommended starting dose for
adherence, enhance pain management, and decrease the FBSF is 200 mcg, and the dose can be increased
likelihood of medication errors. Extended-release hydromor- as needed by applying additional films, up to
phone should be used cautiously in patients with hepatic 800 mcg. The FDA-approved dosing is no more
and renal impairment, two to four-fold increases in plasma than one film be used per episode, separated by
levels have been observed in these populations; consider at least two hours, no more than four doses per
a product which permits greater dosing flexibility. The cost day. Available dosages are 200 mcg, 400 mcg,
and prescription coverage for Exalgo remains unknown at 600 mcg, 800 mcg, and 1,200 mcg. Plasma con-
this time. Therefore, Exalgo provides little advantage over centrations of FBSF and other fentanyl products
other currently available long-acting opioid preparations, may be increased with the co-administration of
and its use should be reserved for patients who cannot cytochrome P 450 (CYP) 3A4 isoenzyme inhibi-
tolerate or do not have adequate analgesia with other long- tors, and concomitant use should be avoided
acting opioid preparations. Additional studies that address due to the risk of increased drug plasma concen-
comparative efficacy to other long-acting opioids and phar- trations. The addition of FBSF provides another
macoeconomic analyses are warranted. There is a black option for patients suffering from breakthrough
box warning on this product flagging its potential for abuse, pain. However, its efficacy in comparison to other
misuse, addiction and criminal diversion and limits its use transmucosal fentanyl preparations is unknown.
to opioid tolerant patients. The warning also calls attention Onsolis is contraindicated in opioid non-tolerant
to the extended-release delivery system which is defeated patients, patients with acute or post-operative

58 america’s Pharmacist | January 2011 www.americaspharmacist.net

pain (includes migraine and other headache as an adjunct to other analgesics commonly used for PHN
pain, emergency department use) and known hy- (such as pregabalin). However, cost of therapy ($675 for one
persensitivity to fentanyl. Onsolis carries a black patch) and need for application by a trained provider may
box warning for abuse potential, patient selection limit its use.
and calls out potential for respiratory depression
when used with a CYP3A4 inhibitor. Onsolis is Diclofenac
available only through a restricted distribution The use of compounded topical NSAIDs has been com-
program, called FOCUS that requires patient, mon practice for many years for the treatment of localized
prescriber and pharmacy enrollment. pain. Several commercial preparations of topical NSAIDs
have recently been approved, all of which contain diclof-
Topical Agents enac. The first preparation on the market was diclofenac
Capsaicin 8 Percent Topical Patch (Qutenza) epolamine 1.3 percent topical patch (Flector) which is
Postherpetic neuralgia (PHN) is a form of neuro- approved for acute mild to moderate pain due to minor
pathic pain that occurs after an outbreak of herpes strains, sprains, or contusions. Each patch contains 180
zoster (shingles). Pain associated with PHN can mg of diclofenac epolamine and should be applied to the
last for months after the infection has cleared affected area twice a day. The patch should not be applied
and can be associated with significant depres- to irritated or broken skin. In October 2007, diclofenac
sion, anxiety, and disruption of sleep patterns. sodium 1 percent gel (Voltaren Gel) was approved for the
The incorporation of the herpes zoster (Zostavax) treatment of osteoarthritis of the upper and lower extremi-
vaccine into the Center for Disease Control and ties. The recommended dosage is 2 grams for each elbow,
Prevention’s (CDC) Advisory Committee on Im- hand, or wrist and 4 grams for each knee, ankle, or foot,
munization Practices (ACIP) adult immunization applied four times daily. The gel is applied using the includ-
guidelines will likely decrease the incidence of ed dosing card and can be used for gel application. The
shingles. However, in those patients who de- maximum daily dose is 32 grams over all affected joints. An
velop PHN, pain management can be difficult. A additional diclofenac preparation was approved in Novem-
mainstay of PHN management is topical capsa- ber 2009 which contains diclofenac sodium 1 percent as
icin but often, patients are not compliant with the a topical solution (Pennsaid) for the treatment of the signs
frequent and persistent application required to and symptoms of knee osteoarthritis. The recommended
achieve analgesia. A topical patch of 8 percent dose is 40 drops applied to each affected knee four times
capsaicin (Qutenza) has been developed for the daily, and the patient should be educated on applying 10
management of neuropathic pain associated with drops at a time, either into the hand or directly onto the
PHN. Qutenza produces its analgesic effects by knee, and the dose should be spread around the knee be-
interacting with transient receptor potential vanil- fore the next 10 drops are applied. Patients should also be
loid 1 receptors (TRPV1). The initial activation of instructed to wait at least 30 minutes after the application
these receptors produces a burning sensation before bathing. Additionally, patients should be educated
due to their pro-nociceptive effects; however, over about systemic adverse effects associated with NSAIDs,
time and after continuous activation, their activ- particularly with long-term use. These include increased
ity decreases and results in desensitization or risk of serious cardiac thrombotic events, MI and stroke
analgesia. Qutenza is applied to the affected area, and serious gastrointestinal adverse events. In post-mar-
pretreated with a local anesthetic, under physician keting reports, the FDA identified cases of diclofenac-in-
supervision, or by health care professionals under duced hepatotoxicity with the use of Voltaren Gel; therefore,
close physician supervision, for 60 minutes and it is recommended that when using any topical diclofenac
can be reapplied no more often than every three preparations, liver functions tests be assessed after four
months. Evidence from an intention-to-treat analy- to eight weeks of therapy and periodically thereafter. No
sis suggested that the analgesic effect of Qutenza diclofenac preparation should be used in the peri-oeprative
can last for up to 12 weeks. Qutenza can be used setting of coronary artery bypass graft (CABG) surgery.

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Multimodal Analgesics sive, dosing of this fat-soluble vitamin for pain is
Tapentadol (Nucynta) not clearly defined. Some of the most aggressive
Approved in 2009, tapentadol is a centrally-acting analgesic regimens of vitamin D range from 5,000 IU/day to
that inhibits the reuptake of NE and acts as an agonist at 50,000 IU/day for limited periods of time.
the mu-opioid receptor. Tapentadol is FDA-approved for the Researchers have found that daily supple-
relief of moderate to severe acute pain in patients age 18 mentation of less than 800 IU was no better than
and older and has been studied in postsurgical models of placebo in the evaluation of muscle strength.
pain as well as in patients with end-stage osteoarthritis who Based on available evidence, an appropriate initial
experienced acute exacerbations of pain. In clinical trials, vitamin D dose would be a compromise between
tapentadol was shown to be noninferior to oxycodone 10 a dose greater than 800 IU/day and the more
mg when given at doses between 50–75 mg every four to six aggressive dosing regimens entailing 5,000 IU/
hours and had a lower incidence of gastrointestinal ad- day. This dose should be titrated based on toler-
verse effects (such as nausea and vomiting). The maximum ability and response. Patients should be advised
recommended dose per day is 600 mg. However, on the first that individual responses to this vitamin may vary.
day of therapy, patients can take one additional dose one Some patients may notice improvements in their
hour after the initial dose, for a total daily dose of 700 mg. It pain symptoms within a few weeks, while others
is proposed that tapentadol lacks 5-HT reuptake inhibition; may not see results for nine months or longer. The
patients who were on stable doses of selective serotonin long-term use of vitamin D, when used at doses
reuptake inhibitors (SSRIs) for at least 28 days were included higher than those recommended for deficiency,
in clinical studies on tapentadol, and no occurrences of 5-HT have not yet been fully investigated.
syndrome were identified. Tapentadol has also been studied
in combination with SNRIs in a 90-day tolerability trial, and Opioid Antagonists
incidences of 5-HT syndrome or noradrenergic hyperactiv- Opioid antagonists have been used to reverse
ity were not reported. However, the manufacturer includes the toxic effects of opioids by displacing them
precautions specifically about the potential risk of 5-HT from their respective receptors. Animal studies
syndrome in its prescribing information based on preclinical have demonstrated that low doses of naltrexone
studies, and use of MAOI within 14 days is contraindicated. may stimulate the up-regulation of mu-opioid re-
Tapentadol is a scheduled II substance, and a detailed ceptors in areas of the brain that control nocicep-
patient history should be conducted to assess the risk of tive responses, and may “reset” existing recep-
misuse and abuse for this medication. An extended-release tors to minimize opioid tolerance. Naloxone was
formulation of tapentadol is currently being studied, along originally synthesized in 1960. Its short duration
with the use of this drug for chronic pain syndromes. of action made it useful for the reversal of opioid
toxicity. Naltrexone was developed soon after, of-
New Strategies fering the advantage of good oral bioavailability,
New Uses for Old Drugs a longer duration of action, and twice the potency
Vitamin D of naloxone. The proposed dosing for pain man-
The role of vitamin D in pain management is unclear, and agement, in combination with opioid agonists, is
the evidence to support its use in chronic pain is poor. It is at a much lower dose than what is recommended
known that hypocalcemia due to vitamin D deficiency induc- for addiction therapy and opioid overdose. Gan
es the secretion of parathyroid hormone, which stimulates et al reported a study using two small doses of
the breakdown of bone to enhance the release of calcium. naloxone together with intravenous morphine in
This breakdown of bony surfaces may lead to characteristic 60 patients in a post-anesthesia care unit. From
complaints of dull and persistent musculoskeletal aches this study, they concluded that naloxone signifi-
and pains. Indications of defective bone mineralization cantly reduced opioid-related adverse effects
may include muscle weakness, fatigue, poor appetite and and reduced post-operative opioid requirements
paresthesias. While vitamin D is well-tolerated and inexpen- for pain control. Other trials and case reports

60 america’s Pharmacist | January 2011 www.americaspharmacist.net

support the safety and efficacy of low-dose or liquids. This formulation is proposed to prevent oxyco-
ultra-low-dose opioid antagonists for the man- done “dumping” from the capsule when it is ingested with
agement of pain in opioid-tolerant patients. In alcohol, common solvents, or aqueous buffers across a
summary, opioid antagonists offer promising new wide range of pH, rendering oxycodone extraction difficult.
indications that extend beyond their role in opioid Remoxy has not been studied in head-to-head trials with
reversal and addition. other extended-release opioids; therefore, it is unknown if
the formulation sustains or reduces the efficacy of oxyco-
New Strategies done and if the tamper-resistant mechanism contributes to
Abuse-Deterrent and Tamper-Resistant tolerability issues. The manufacturer is targeting to resubmit
Opioid Formulations a new drug application (NDA) for Remoxy after gathering
The misuse, abuse, and diversion of opioids pose additional stability data.
significant challenges for health care professionals
who must evaluate the appropriate use of opioids OxyContin Reformulation
and their potential abuse. The abuse of prescrip- A reformulation of OxyContin was approved for marketing
tion drugs is a growing public health concern that in April 2010 and will utilize a polymer that makes the tab-
has gained the attention of several pharmaceutical lets difficult to break or crush. When introduced to a liquid,
companies who have reformulated many common- the formulation transforms into a viscous gel that resists ex-
ly used opioids to prevent drug abuse. The ideal traction of oxycodone for injection. The manufacturer will be
dosage form would resist tampering by any method required to conduct post-marketing studies on the extent
while still offering therapeutic effectiveness. of misuse and abuse of the new formulation and will have
a REMS that requires a medication guide to be dispensed
Embeda with the medication, along with required prescriber educa-
Embeda (King Pharmaceuticals) is extended-re- tion on the use of opioids for pain.
lease morphine sulfate with sequestered naltrex-
one that was approved for marketing in 2009 and Opioid REMS
is formulated as pellets contained in a capsule. Due to the risks associated with opioid analgesics, the FDA
Each pellet contains a sequestered naltrexone has requested the inclusion of long-acting and extended-
core surrounded by morphine. When ingested release opioid class REMS proposals with the submission of
orally, morphine is absorbed but the naltrexone any new drug application. This is to ensure that the benefits
core remains intact, and no or little naltrexone of any new opioid or formulation outweigh its risks, with the
is released. However, when this formulation is ultimate goal of reducing opioid abuse and diversion. Cer-
crushed, the euphoric effects of morphine are tain opioid analgesics will be required to have REMS. These
blunted because naltrexone is released with mor- include all long-acting formulations and methadone when
phine. In clinical trials, most patients who received used for pain. The REMS for these drugs will include the
Embeda had negligible levels of naltrexone and use of medication guides and implementation of elements
those who had detectable levels had no increase to ensure the safe use of these drugs. Example elements
in pain. Under tampering conditions, this drug re- include requiring prescriber training and certification on the
leases levels of naltrexone that are similar to those proper use of opioids, and requiring pharmacies to become
achieved with immediate-release naltrexone. certified before the dispensing of opioids.

Remoxy Novel Drug Targets

Remoxy is an extended-release formulation of Cannabinoid Receptors
oxycodone awaiting FDA Approval. The formu- The use of Cannabis for medical purposes has increased
lation contains oxycodone in a highly viscous with the passing of legislature in 14 states that allows the
liquid formulation matrix and is intended to resist legalized use of medical marijuana. Delta-9-tetrahydro-
abuse by crushing or by dissolution in common cannabinol (THC), the primary component of marijuana, is

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responsible for its therapeutic, psychoactive, and adverse olizers, which could correlate to supratherapeutic
effects. The concerns with the use of marijuana have sur- concentrations of opioids as well as an inability to
rounded finding an appropriate delivery form. Smoking is convert drugs into their active metabolites (such
the most efficient route of administration, but comes with as codeine into morphine). Identifying CYP2D6
dangers. Growing research has focused on an improved metabolizer status may assist with therapeutic
understanding of the endocannabinoid system to identify decision-making when considering opioid anal-
cannabinoid receptors, leading to the development of gesics for pain. Using the mu1 opioid receptor
synthetic compounds to interact with this system. The first (OPRM1) as a biomarker, variances in alleles
cannabinoid receptor, CB1, was identified in the 1990s and may be identified to possibly assess opioid dose
involves the modulation of several neurotransmitters such requirements. The cost and practicality of such
as dopamine and 5-HT. The activation of the CB1 receptor tests remains unknown, but the idea of personal-
may be responsible for some of the therapeutic effects of ized medicine has the potential to improve the
marijuana but is also associated with impaired cognition safe and effective use of opioids for pain.
and altered motor function. The CB2 receptor was subse-
quently discovered and is not as well-distributed through- Summary
out the body like CB1. Commercially-available cannabi- There are significant challenges associated with
noids such as dronabinol have been studied as analgesics, the management of both acute and chronic pain.
but their use is limited by their adverse effects at thera- The development of new drugs, targets, and
peutic doses. Ongoing research on the endocannabinoid strategies are the first steps towards the safe
system shows promise for the development of drugs that and effective use of analgesics. Several new
can interact with this system while minimizing the unfavor- medications have been introduced to the market
able effects of cannabinoids. within the past few years, and while promising,
their role in pain management continues to be
Pharmacogenomics of Pain unknown. However, the individualistic nature of
There are many factors that play a role in the undertreat- pain warrants the need for several therapeutic
ment of pain. Among the more common reasons, adverse options to ensure an appropriate analgesic regi-
effects and fear of addiction remain significant concerns men for each patient. Emerging science behind
for both providers and patients. The subjective nature of new drug targets and the pharmacogenomics of
pain complicates its treatment, and the use of therapeutic pain will undoubtedly show promise in the future
agents may be used ultra-cautiously, leading to inadequate of pain management and the role of personal-
pain management. The pharmacogenomics of pain may ized medicine. As pharmacists, it is important to
provide an improved understanding of a patient’s individual recognize the current challenges associated with
risks associated specifically with the use of opioids. Be- pain management and to be a resource for other
cause the CYP 450 system plays a role in opioid metabo- clinicians as analgesic options are considered.
lism, variants of enzymes involved in the degradation of Finally, our accessibility as health care providers
opioids (CYP2D6 and CYP2C19) have been linked to their puts us in position to serve as patient advocates
efficacy and toxicity. Additionally, the mu-opioid receptor to address barriers associated with inappropriate
and its subtypes also play a role in the therapeutic and ad- treatment or undertreatment of pain.
verse effects of these agents. Therefore, these biomarkers
have been identified as having relevance in determining a
patient’s risk of adverse effects or toxicity and the potential Michele Matthews, PharmD, is an assistant professor of
for opioids to produce effective analgesia. pharmacy practice at the Massachusetts College of Phar-
With regard to the CYP2D6 isoenzyme, patients may macy and Health Sciences. Matthews also practices as a
be poor, intermediate, extensive, or ultra-rapid metaboliz- clinical pharmacy specialist in pain management and certi-
ers. About 8 percent of Caucasians and 2 percent of Afri- fied pain educator (CPE) at the Brigham and Women’s Pain
can Americans are considered to be CYP2D6 poor metab- Management Center in Boston.

62 america’s Pharmacist | January 2011 www.americaspharmacist.net

Continuing Education Quiz 6. Which one of the following formulations utilizes BioErod-
Select the correct answer. ible MucoAdhesive (BEMA) technology?
a. Pennsaid
1. What is the estimated yearly cost of chronic b. Exalgo
pain in the United States? c. Onsolis
a. $10 million d. Nucynta
b. $100 million
c. $10 billion 7. J.T. is a 64-year-old oncology patient who is stable on
d. $100 billion fentanyl transdermal patches 50 mcg/hr. Which regimen
would be advised to manage breakthrough pain?
2. Which one of the following neurotransmitters a. Onsolis 200 mcg PRN no more than QID
may produce analgesia when its reuptake is b. Onsolis 200 mcg QID PRN, space doses by two hours
inhibited? c. Onsolis 200 mcg no more than four films QID PRN
a. Serotonin breakthrough pain
b. Dopamine d. Onsolis 200 mcg 1–2 films q1hour prn breakthrough
c. Epinephrine pain
d. Norepinephrine
8. Which one of the following statements about Qutenza is
3. Which one of the following may be used as an FALSE?
adjuvant to opioid therapy to manage post-oper- a. It is a high potency capsaicin formulation that needs to
ative pain as an adjunct to opioid analgesics? be applied under the supervision of a trained clinician.
a. Ibuprofen IV following renal transplant b. It can be reapplied every three months and used ad-
b. Ibuprofen IV following totally knee arthroplasy junctively with other analgesics.
c. Ketoprofen IV for a patient with a history of GI c. Its mechanism of action is related to its activity at
bleed on oral NSAIDs TRPV1 receptors.
d. Ketorolac IV following single coronary bypass d. It is indicated for the treatment of the signs and symp-
toms of osteoarthritis.
4. Which one of the following drugs was recently
approved for the management of fibromyalgia? 9. Which one of the following statements is true of Qutenza?
a. Savella a. The Qutenza patch is applied by a health care profes-
b. Qutenza sional and removed by the patient.
c. Caldolor b. T he Qutenza patch may be cut to fit the treatment area.
d. Acurox c. L
 ocal anesthetic use is contraindicated in conjunction
with Qutenza patch application.
5. Which one of the following is TRUE of Exalgo? d. T he Qutenza patch is applied by a health care profes-
a. It is the first twice daily formulation of hydro- sional once monthly for 60 minutes.
morphone.
b. Ambulatory patients should be monitored for 10. Which one of the following is TRUE of a topical formu-
orthostatic hypotension. lation of diclofenac?
c. No dose is adjustment needed for patients a. Local application avoids GI adverse effects
with moderate hepatic impairment. b. Formulations include patch, gel and ointment
d. No dose adjustment is needed for patients c. L
 iver function tests are recommended at four to eight
with moderate renal impairment weeks and periodically thereafter
d. P
 ennsaid should be washed off after 30 minutes to
avoid local irritation.

www.americaspharmacist.net January 2011 | america’s Pharmacist 63

11. Which one of the following is a multimodal analgesic 16. Which one of the following statements with
that inhibits the reuptake of norepinephrine and acts as an regard to the investigational drug, Remoxy is
opioid agonist? TRUE?
a. Dronabinol a. It is a tamper-resistant formulation of immedi-
b. Duloxetine ate-release hydromorphone.
c. Milnacipran b. It is a tamper-resistant formulation of extend-
d. Tapentadol ed-release oxycodone.
c. It is easily dissolvable in common solvents.
12. Which one of the following statements with regard to d. It is co-formulated with disulfiram.
Nucynta is TRUE?
a. It is an extended-release formulation approved for the 17. Which one of the following long-acting opioid
treatment of postherpetic neuralgia. analgesics is conducting post-marketing stud-
b. It was found to be noninferior to oxycodone 10 mg when ies on its reformulation which attempts to curb
given at dosages between 50 to 75 mg. abuse and diversion?
c. It was not studied in combination with selective sero- a. Duragesic
tonin reuptake inhibitors (SSRIs) or serotonin norepi- b. MS Contin
nephrine reuptake inhibitors (SNRIs). c. Opana ER
d. It is a scheduled III controlled substance. d. OxyContin
13. Which one of the following statements with regard to
the use of vitamin D for pain is FALSE? 18. Which one of the following receptors may
a. T he recommended dose for the treatment of chronic produce analgesia but also unfavorable adverse
pain is 400 IU/day. effects including impaired cognition and altered
b. Response to therapy will vary between patients. motor function?
c. Its long-term use for chronic pain has not been evalu- a. Alpha-2 adrenergic receptor
ated. b. Cannabinoid receptor
d. It may be effective for the treatment of symptoms as- c. TRPV1 receptor
sociated with impaired bone mineralization. d. Vanilloid receptor

14. Which one of the following therapeutic classes is being 19. Which one of the following opioid receptors
considered for use in pain management as an adjunct to may contribute determining individual opioid
opioid analgesics to “reset” opioid receptors and minimize dose requirements?
opioid tolerance? a. Delta receptor
a. Anticonvulsants b. Kappa receptor
b. Beta-blockers c. Mu receptor
c. NSAIDs d. Sigma receptor
d. Opioid antagonists
20. Which one of the following patient factors
15. Which one of the following is an abuse-deterrent opioid may explain supratherapeutic concentrations of
preparation that is formulated as extended-release mor- opioid analgesics such as morphine?
phine with sequestered naltrexone? a. Being an CYP2D6 ultra-rapid metabolizer
a. Embeda b. Being a CYP2D6 poor metabolizer
b. Exalgo c. Being of Asian decent
c. Remoxy d. Being of Hispanic decent
d. Onsolis

64 america’s Pharmacist | January 2011 www.americaspharmacist.net

 Innovations in Pain Management: New Drug
21. Which one of the following biomarkers may Developments, Targets, and Strategies for Safe
assist in choosing personalized opioid regimens and Effective Analgesia
in the future? Jan. 3, 2011 (expires Jan. 3, 2014) • Activity Type: Knowledge-based

a. CYP1A2
FREE ONLINE C.E. Pharmacists now have online access to NCPA’s
b. TRPV1 C.E. programs through Powered by CECity. By taking this test online—
go to the Continuing Education section of the NCPA Web site (www.
c. OPRM1 ncpanet.org) by clicking on “Professional Development” under the
d. CB1 Education heading you will receive immediate online test results and
certificates of completion at no charge.

22. Which is the correct drug-receptor pairing? To earn continuing education credit: ACPE Program 207-000-011-001-H01-P
a. Milnacipran/COX-2 A score of 70 percent is required to successfully complete the C.E. quiz.
b. Diclofenac/Vanilloid receptor If a passing score is not achieved, one free reexamination is permitted.
Statements of credit for mail-in exams will be available online for you
c. Tapentadol/TRPV1 receptor to print out approximately three weeks after the date of the program
d. naltrexone/Mu receptor (transcript Web site: www.cecerts.ORG). If you do not have access to a
computer, check this box and we will make other arrangements to send
you a statement of credit: q

Record your quiz answers and the following information on this form.
q NCPA Member License
NCPA Member No. ____________________ State __________ No. _____________________
q Nonmember State __________ No. _____________________

All fields below are required. Mail this form and $7 for manual processing to:
NCPA C.E. Processing Ctr.; 405 Glenn Drive, Suite 4; Sterling, VA. 20164
_____________________________________________________________________________________
Last 4 digits of SSN MM-DD of birth
_____________________________________________________________________________________
Name
_____________________________________________________________________________________
Pharmacy name
_____________________________________________________________________________________
Address
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City State ZIP
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_____________________________________________________________________________________
Store e-mail (if avail.) Date quiz taken

Quiz: Shade in your choice

a b c d e a b c d e
1. q q q q q 12. q q q q q
2. q q q q q 13. q q q q q
3. q q q q q 14. q q q q q
4. q q q q q 15. q q q q q
5. q q q q q 16. q q q q q
6. q q q q q 17. q q q q q
7. q q q q q 18. q q q q q
8. q q q q q 19. q q q q q
9. q q q q q 20. q q q q q
10. q q q q q 21. q q q q q
11. q q q q q 22. q q q q q
Quiz: Circle your choice
23. Is this program used to meet your mandatory C.E. requirements?
a. yes b. no
24. Type of pharmacist: a. owner b. manager c. employee
 ge group: a. 21–30 b. 31–40 c. 41–50 d. 51–60 e. Over 60
25. A
 id this article achieve its stated objectives? a. yes b. no
26. D
27. H
 ow much of this program can you apply in practice?
a. all b. some c. very little d. none

How long did it take you to complete both the reading and the quiz? ______ minutes
NCPA® is accredited by the Accreditation Council for Pharmacy Education as a provider
of continuing pharmacy education. NCPA has assigned 1.5 contact hours (0.15 CEU)
www.americaspharmacist.net of continuing education credit to this article. Eligibility to receive continuing education
credit for this article expires three years from the month published.