Topics in

PAIN MANAGEMENT
Vol. 31, No. 7 Current Concepts and Treatment Strategies February 2016

CME ARTICLE
Use of Topical Pain Medications in the Treatment of Various
Pain Syndromes
Sahar Z. Swidan, PharmD, and Hagar A. Mohamed, MS
Learning Objectives: After participating in this CME activity, the physician should be better able to:
1. Explain why topical pain medications are safer than oral forms and describe the differences between topical and transder-
mal formulations.
2. List the available dosage forms for pain management through compounding.
3. Discuss treatment choices for each type of pain on the basis of the pathophysiological classification of pain and clinical
studies on treatment options for various pain conditions.
4. Provide insight about the future of topical pain medications.
Key Words: Analgesic gels, Analgesic ointments, Compounded pain medications, Nifedipine, Topical analgesics, Transdermal analgesics

T opical pain formulations have wide popularity among

health care providers and patients when they are used, but
there are indications that not all providers are familiar with
how best to prescribe them and use them. For those who do
prescribe and use topical formulations, this popularity is
In This Issue
primarily because this method of medication delivery avoids
systemic effects (ie, gastrointestinal adverse effects and first-
pass hepatic metabolism).1 Oral formulations are responsible
for 2% to 4% of the incidence rate of gastrointestinal ulcer
and other severe complications annually. This rate translates
into a fourfold increase in the incidence of serious gastrointes-
tinal adverse events for those using oral formulations, com-
pared with nonusers.2-7

Use of Topical Pain Medications in the Treatment of

Various Pain Syndromes . . . . . . . . . . . . . . . . . . . . . . 1
CDC Releases Guidelines for Public Comment and
Data Showing Drug Overdose Deaths at Record
Numbers for 2014 . . . . . . . . . . . . . . . . . . . . . . . . . . 9
BESTFIT Studies Analyze Sleep Medications Role in
Improving Fibromyalgia Patient Outcomes . . . . . . . . 10
CME Quiz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Dr. Swidan is Clinical Associate Professor of Pharmacy, University of
Michigan College of Pharmacy, and, Chief Executive Officer, Pharmacy
Solutions, 5204 Jackson Rd, Ste C, Ann Arbor, MI 48103, E-mail:
sswidan@med.umich.edu; and Mrs. Mohamed is a Pharmacist and
Researcher, Ann Arbor, Michigan.
The authors and all staff in a position to control the content of this
CME activity have disclosed that they and their spouses/life partners (if
any) have no financial relationships with, or financial interests in, any
commercial companies pertaining to this educational activity.
The authors have disclosed that the use of topical pain medications in
combination as described in this article has not been approved by the
FDA. Please consult the product labeling for approved uses.

Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide
continuing medical education for physicians.
Lippincott Continuing Medical Education Institute, Inc., designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits.
Physicians should only claim credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the CME
article and complete the quiz and evaluation assessment survey on the enclosed form, answering at least 70% of the quiz questions correctly. This activity
expires on January 31, 2017.

1
Topics in Pain Management February 2016

INTERIM EDITOR Topical formulations may be favored because of efficient

local delivery of medications.1 Lin et al8 compared the efficacy
Elizabeth A.M. Frost, MD of topical formulations with oral medications and placebo in
Professor of Anesthesiology treating osteoarthritis pain over a 4-week period. Although oral
Icahn School of Medicine at Mount Sinai medications were found to be more effective than topical for-
New York, NY mulations in weeks 3 and 4, topical formulations demonstrated
ASSOCIATE EDITOR superiority in efficacy during the first 2 weeks of treatment,
compared with placebo.
Anne Haddad Limited use of resources available for topical pain medica-
Baltimore, MD tions, particularly compounded pain medications, by pain cli-
EDITORIAL BOARD
nicians is regarded as a lost chance at another option for pain
management. A study of 120 pain clinicians revealed that only
Jennifer Bolen, JD 27% reported frequently prescribing compounded topical pain
The Legal Side of Pain, Knoxville, TN
medications, with a success rate of 47%.9 For that reason, this
Michael DeRosayro, MD article aims to provide a comprehensive overview of topical
University of Michigan, Ann Arbor, MI
pain medications used in acute and chronic pain management,
James Dexter, MD highlighting evidence-based compounding ideas and resources.
University of Missouri, Columbia, MO
Claudio A. Feler, MD
University of Tennessee, Memphis, TN
Topical and transdermal are not
Alvin E. Lake III, PhD
Michigan Head Pain and Neurological Institute, Ann Arbor, MI always interchangeable terms.
Daniel Laskin, DDS, MS
Medical College of Virginia, Richmond, VA
Vildan Mullin, MD Dosage Forms Available for Pain
University of Michigan, Ann Arbor, MI Management Through Compounding
Alan Rapoport, MD Compounding pharmacies can produce medications in vari-
New England Center for Headache, Stamford, CT
ous forms. Topical formulations include creams, ointments,
Gary Ruoff, MD
West Side Family Medical Center, Kalamazoo, MI
The continuing education activity in Topics in Pain Management is intended for clinical
Frederick Sheftell, MD and academic physicians from the specialties of anesthesiology, neurology, psychiatry,
physical and rehabilitative medicine, and neurosurgery as well as residents in those fields
New England Center for Headache, Stamford, CT and other practitioners interested in pain management.
Stephen Silberstein, MD Topics in Pain Management (ISSN
0882-5646) is published monthly by
Jefferson Headache Center, Philadelphia, PA Lippincott Williams & Wilkins, 16522
Hunters Green Parkway, Hagerstown, MD
Steven Silverman, MD 21740-2116. Customer Service: Phone (800) 638-3030, Fax (301) 223-2400, or Email
Michigan Head Pain and Neurological Institute, Ann Arbor, MI customerservice@lww.com. Visit our website at lww.com.
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved. Priority postage paid
Sahar Swidan, PharmD, BCPS at Hagerstown, MD, and at additional mailing offices. GST registration number:
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yright. Reproduction, photocopying, and storage or transmission by magnetic or electronic
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PAID SUBSCRIBERS: Current issue and archives (from 1999) are now available FREE
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Topics in Pain Management is independent and not affiliated with any organization, vendor
or company. Opinions expressed do not necessarily reflect the views of the Publisher, Editor, or
Editorial Board. A mention of products or services does not constitute endorsement. All com-
ments are for general guidance only; professional counsel should be sought for specific situa-
tions. Editorial matters should be addressed to Anne Haddad, Associate Editor, Topics in Pain
Management, 204 E. Lake Avenue, Baltimore, MD, 21212; E-mail: anne.haddad1@gmail.com.
Topics in Pain Management is indexed by SIIC (Sociedad Iberoamericana de Informacin
Cientfica).

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Topics in Pain Management February 2016

Table 1. Comparison Between Topical and in treating sacral sores, with 10 mg once daily with occlusive
Transdermal Formulations dressing. The medication was well tolerated, and no systemic
effects were reported.11
Topical Transdermal Similarly, in chemotherapy-associated mucositis, 15 mL of
Minimal systemic High local concentration and 2% morphine was found superior to magic mouthwash, con-
absorption and significant systemic absorption taining a mixture of equal parts of lidocaine, diphenhydramine,
consequently less and magnesium aluminum hydroxide, applied 6 times per day.
systemic side effects Morphine decreased the duration of pain and severity and
May administer Pharmacokinetic functional dysfunction.12
multiple drugs in Tachyphylaxis to topical morphine develops within 3 days.
Associated with metabolism
one dosage form However, an N-methyl-D-aspartate (NMDA) antagonist (keta-
Disposition of a drug is similar mine) was demonstrated to reverse tolerance in mice.13
in transdermal and oral Moreover, concomitant use of topical cannabinoids increased
formulations of the same drug efficacy in mice at the nociceptive points.14
Example: transdermal application
of diclofenac sodium gel
480 mg/d reaches up to 19.7%
of the AUC of oral diclofenac Neuropathic pain can be treated with
150 mg/d
capsaicin, tricyclic antidepressants,
Treatment is focused Requires small molecular sizes
on peripheral and lipophilicity to penetrate anticonvulsants, and local anesthetics.
ganglia stratum corneum
Vehicles such as iontophoresis
and photophoresis act as Neuropathic Pain
penetration enhancers10 Neuropathic pain can be treated with capsaicin, tricyclic
AUC, area under the curve. antidepressants, anticonvulsants, and local anesthetics.
Capsaicin
and gels; transdermal patches; medication sticks; and solu- Before applying high-dose capsaicin, pretreat the area with
tions, suspensions and sprays. Topical and transdermal local anesthetic (eg, lidocaine). Then, apply patch for up to
are not always interchangeable terms. An illustration of the 60 minutes, up to 4 patches at a time, once every 3 months at
differences between topical and transdermal formulations is the providers office.15,16
provided in Table 1. Oral formulations include capsules;
drops, solutions, suspensions, and syrups; and troches, gum- Tricyclic Antidepressants
mies, and sublingual tablets. Other formulations include sup- Another treatment option is tricyclic antidepressants, such as
positories, intranasal, and inhaled formulations. amitriptyline. Lockhart17 demonstrated the efficacy of amitripty-
line 4% and ketamine 2% versus amitriptyline 2% and ketamine
1% versus placebo.
Nociceptive pain can be treated with The authors stated that the higher dose combination signifi-
cantly lowered pain intensity, with more subjects attaining
salicylate; NSAIDs; capsaicin; opioids; 30% reduction in pain. On the basis of these findings, they
or local anesthetics. recommend the use of higher doses coupled with ketamine for
longer periods for dull, chronic pain. In clinical practice,
we always recommend starting with the lower dose and
slowly titrating upward if needed. Moreover, practitioners
Treatment Choices Based on Pathophysiologic
should exercise caution regarding potential cardiac adverse
Classification of Pain
effects, such as QT prolongation, and take into account
Nociceptive Pain whether the patient is concurrently taking other QT-prolonging
Nociceptive pain can be treated with salicylate; nonsteroidal medications.
anti-inflammatory drugs (NSAIDs); capsaicin; opioids, such Nevertheless, other clinical studies did not demonstrate effi-
as morphine; or local anesthetics. cacy in neuropathic pain as reported in the Lynch et al.18,19
A randomized, double-blind, placebo-controlled, crossover studies. Variability in response, especially in pain manage-
pilot study demonstrated the effectiveness of topical morphine ment, is present in other treatment modalities also.

2016 Wolters Kluwer Health, Inc. All rights reserved. 3

Topics in Pain Management February 2016

however, many trials already

If topical anesthetics are overprescribed and overapplied,
patients are prone to serious cardiac side effects, such as
arrhythmias.
Anticonvulsants
A retrospective study of 51 patients using 2%, 4%, or 6% gabap-
entin cream (in Lipoderm base) 3 times daily for 8 weeks demon-
strated a 4- to 5-point reduction in pain scores on a 10-point pain
scale (P < 0.001). No systemic side effects were reported.20,21
Local Anesthetics
Recent studies continue to demonstrate the effectiveness of
5% lidocaine patches in treating neuropathic pain.22 Similarly,
another study23 recommended the use of three 5% lidocaine
patches for 12 hours every day for treating refractory peripheral
neuropathic pain. In this study, 13 of the 16 study participants
reported relief, and 15 participants continued to use lidocaine
patches for an average of 6.2 weeks, with only 1 patient discon-
tinuing treatment because of inefficacy. Rare systemic side
effects were reported.
Topical lidocaine gel was also found beneficial in managing
postherpetic neuralgia in 39 patients, with no systemic adverse
effects reported and blood levels measured less than 6 g/mL.24
However, extreme caution should be exercised when using topi-
cal anesthetics because concentration of each agent and amount
applied topically is critical to factoring in maximum allowed
amounts. If topical anesthetics are overprescribed and overap-
plied, patients are prone to serious cardiac side effects, such as
arrhythmias. National guidelines exist as to maximum concentra-
tion and amount of each agent that can be topically applied safely.
More research is needed on the efficacy of ketamine;
however, many trials already have demonstrated efficacy
of IV ketamine.
NMDA Antagonists
Quan et al26 found that ketamine 5% gel applied 2 to 3 times
daily was effective in providing pain relief in 16 of 23 patients lidocaine (70 mg) and tetracaine (70 mg). The patches
with postherpetic neuralgia. Seven patients started other medi-
cations simultaneously and 2 reported transient skin irritation. to air.32 The effect of the 2 local anesthetics on reducing
25
Additionally, Gammaitoni et al demonstrated the efficacy of
topical ketamine in managing mixed neuropathic pain 15 min-
utes after its administration, with no systemic side effects
reported. More research is needed on the efficacy of ketamine;
have demonstrated efficacy of IV
ketamine.
Osteoarthritis Pain
The effectiveness of topical
morphine in managing chronic
pain in patients with knee osteo-
arthritis (OA) was demonstrated by Wilken et al.27 However,
safety concerns may hinder its use for long-term management
of knee pain. Systemic absorption of topical morphine is gener-
ally less than with oral administration. Nonetheless, topical mor-
phine appeared in the urine of study patients. Quantitative data
indicating the extent of systemic absorption caused by topical
formulations are needed.27
Other conventional and safer therapies have demonstrated
effectiveness in treating chronic knee pain of OA.28 Recently,
3 topical cyclooxygenase (COX) inhibitors were approved for
treatment of chronic pain:
1. Diclofenac sodium gel 1% for OA pain;
2. Diclofenac epolamine 1.3% topical patch for acute mus-
culoskeletal pain; and
3. Diclofenac 1.5% topical solution for OA of the knee.
Niethard et al29 analyzed the use of 1.16% diclofenac topical
gel applied 4 times a day in 237 patients with chronic knee
pain associated with OA. The duration of this double-blind
study was 3 weeks, and diclofenac was significantly superior
to placebo in reducing pain (P = 0.03).
Superficial Musculoskeletal Structures
Shoulder bursitis, a nonarthritic shoulder pain, can be addressed
adequately with topical analgesics (eg, NSAIDs), in addition to
other measures such as rest, ice,
corticosteroid injections, and
physical therapy.30
Bursitis was explained as a
mechanism of shoulder impinge-
ment syndrome (SIS). A pilot
study and case reports first reported
potential use of heated lidocaine/
tetracaine patches in alleviating
SIS.30,31 For a period of 42 days,
60 patients were recruited to test the effectiveness of heated
lidocaine/tetracaine patches containing eutectic mixture of
included a heating component that is activated upon exposure
peripheral pain transmission via ion and glutamate pathways
was equal to that of invasive subacromial corticosteroid injec-
tions. In this study, patients were directed to use the patch twice
a day for 4 hours.

4 2016 Wolters Kluwer Health, Inc. All rights reserved.

Topics in Pain Management February 2016

disappeared, according to the

Extreme caution must be used with heated lidocaine/ patient.34

tetracaine, as heat can increase the absorption of most drugs, Diabetic Neuropathy

and cardiac toxicity may be a potential adverse reaction with Topical capsaicin cream has
been frequently used in treating
anesthetic agents. musculoskeletal pain and dia-
betic neuropathy.42 Studies since
1992 indicated the effectiveness
Extreme caution must be used with heated lidocaine/tetracaine, of topical 0.075% capsaicin cream applied 4 times a day in
as heat can increase the absorption of most drugs, and cardiac patients with diabetic neuropathy not responsive to conven-
toxicity may be a potential adverse reaction with anesthetic tional therapies.43
agents. Attempts to enhance patient adherence to treatment with
capsaicin patches have included a single application of a high
Complex Regional Pain Syndrome dose (eg, 8% capsaicin patchesQutenza). There is limited
Complex regional pain syndrome (CRPS) can be treated evidence with regard to the effectiveness42 and safety of high-
with NSAIDs; 2 agonists, such as clonidine; tricyclic antide- dose capsaicin formulations in diabetic neuropathy, and
pressants; anticonvulsants; local anesthetics; or NMDA antag- results discourage its use in patients with painful diabetic neu-
onists, such as ketamine. It is critical to consider these factors ropathy and painful HIV-associated neuropathy.44
in patients with CRPS, particularly because there are no drugs A recent 2-arm, double-blind, randomized, placebo-controlled
approved specifically for CRPS.33 Hence, patients with CRPS clinical trial investigated the potential therapeutic effects of the
might require trials of several medications before adequate fruit extract of Citrullus colocynthis (known as bitter apple).
pain control is achieved. Results were promising, with the study drug demonstrating a
Davis et al34 demonstrated the efficacy of clonidine in sympathet-significant difference in pain relief compared with placebo
ically maintained pain (CRPS) when they analyzed its effect on 6 (P < 0.001) in patients with diabetic neuropathy.45
patients in an open-label case series. Two to 7 Catapres-TTS-2 and Compounded topical creams play an outstanding role in
TTS-3 patches were applied for 2 to 10 days. Four of the patients serving the needs of patients with diabetic neuropathy-associated
experienced reduced hyperalgesia. However, injection of norepi- pain. In 2015, a study demonstrated good to excellent results
nephrine or phenylephrine rekindled hyperalgesia in 2 patients. in relief of pain associated with diabetic neuropathy and relief
A case study35 highlighted critical aspects that clinicians must of other chronic neuropathic pain with the use of the com-
consider in planning a treatment modality for their patients. pounded 6B and 7B creams. Both of these preparations con-
These include interindividual variations and the resultant supe- tain ketamine (10%); baclofen (2%); gabapentin (6%);
rior efficacy that topical formulations often demonstrate over amitriptyline (4%); bupivacaine (2%); and clonidine (0.2%).
oral medications in some patients. This case study modeled Nifedipine (2%) was added to the 7B cream. Use of the 6B and
this concept in setting up a multimodal stepped care approach 7B creams resulted in a reduction in the need for oral analgesics
using topical analgesics for severe intractable neuropathic pain and referrals made by physicians to pain specialists.46 However,
in a 42-year-old white man diagnosed with CRPS. Several tri- the doses administered in the 2015 study were slightly higher
als with high-dose gabapentin, pregabalin, tramadol, and than those in other studies that have reported good efficacy.
NSAIDs were found to be ineffective. Tramadol resulted in Agents that increase circulation are beneficial in diabetic
patient hospitalization secondary to opioid-induced ileus. neuropathy. These agents include the following:
Topical amitriptyline was chosen as the main therapeutic regi-
Nifedipine transdermal: new technologies ensure higher
men for the patient in the case study after his clinical response to
drug concentrations at the target site without irritation and
oral amitriptyline 25 mg.35 Amitriptyline 5% cream applied
erythema;47
3 times a day resulted in 30% enhancement of pain relief after
1 month. Therefore, several documented effective topical analge- Pentoxifylline transdermal; and
sics were added to the formula-
tion: topical ketamine 10% cream36,37
and later dimethyl sulfoxide 50%
as a penetration enhancer38 and
Because significant hypotension is a serious adverse reaction
for its reported possible effective- with oral dosing of nifedipine, topical nifedipine is better
ness in CRPS.39-41 After 8 months
of therapy, applying the cream tolerated transdermally.
only once daily, the pain almost

2016 Wolters Kluwer Health, Inc. All rights reserved. 5

Topics in Pain Management
Compounded Topical
Formulations for Pain
For arthritistransdermal formulation:
Ketoprofen 10%;
Ketamine 2.5%, ketoprofen 10%, and lidocaine 2%; or
Ketoprofen 10%, methylsulfonylmethane 10%.
For neuropathic pain:
CRPSamitriptyline 2%/ketoprofen 5%/ketamine
5%, gabapentin 3%, clonidine 0.1%;
Ketoprofen 10%, ketamine 5%, lidocaine 2%;
Intranasal ketamine 10% solution; or
Amitriptyline 2%/gabapentin 3%, ketoprofen 10%,
lidocaine 2%, and ketamine 10% cream. A case study
demonstrated success of this formulation in treating
postherpetic neuralgia in a patient who was nonre-
sponsive to standard treatments.57
-Lipoic acid (thioctic acid): 300 to 600 mg daily orally
modulates nitric oxide within cells, stimulates glucose
uptake by muscle cells, and helps prevent diabetic neu-
ropathy by decreasing lipid peroxidation of nerve
tissue.48
Raynaud Syndrome
Raynaud syndrome can be treated with calcium channel-
blockers (eg, nifedipine49,50 or pentoxifylline 5% to 15%51).
For nifedipine taken orally 10 to 20 mg 3 times a day,50
adverse effects were noted in one third of study participants
(headache, flushing, dizziness, reflex tachycardia, and periph-
eral edema). The recommended transdermal concentrations of
nifedipine are 0.2% to 0.5% cream. Because significant hypo-
tension is a serious adverse reaction with oral dosing of nifedi-
pine, topical nifedipine is better tolerated transdermally.
Anal Fissures and Spasms
Studies estimate that 30% to 40% of the population experi-
ences a proctologic pathology at least once. Recently, there
has been a shift in the management of anal fissures from sur-
gery to pharmacologic measures that include nifedipine,
diltiazem 3%, and bethanechol 0.1%.52-55
Nifedipine was administered at the dose of 20 mg orally twice
daily for 8 weeks, and 9 of the 15 patients were healed with
flushing and headache reported as side effects.53 In a study com-
paring the previous oral dose with nifedipine 0.2% topical gel
administered every 12 hours for 21 days, 95% total remission
was achieved.54
6 2016 Wolters Kluwer Health, Inc. All rights reserved.
February 2016
Vulvodynia
Topical treatments have also been used with success to treat
vulvodynia. Formulations used include amitriptyline 2%/
baclofen 2%56 and gabapentin 3% to 6%.20
Future of Topical Pain Medications
Rapidly progress is being made to enhance therapeutic action
by optimizing delivery of active ingredients in topical formu-
lation administered on the skin and on the buccal mucosa.
Sanz et al58 outlined the currently available techniques in phar-
maceutical design to improve drug topical and buccal bioavail-
ability through modifying chemical and physical factors and
introducing novel dosage forms, such as vesicles, cyclodex-
trins, nanoparticles, and other complex systems. In addition,
they suggested integrating the previous techniques.
The use of electricity (iontophoresis)
and ultrasound (phonophoresis)
greatly enhances the permeation of
topical active ingredients across the
stratum corneum.
It was proved that incorporating propylene glycol and
hydroxypropyl -cyclodextrin as penetration enhancers, with
lornoxicam into a topical gel formulation, resulted in compara-
ble analgesic effect to lornoxicam injection (Xefo) in an in vitro
study.59
In addition, the use of electricity (iontophoresis) and ultra-
sound (phonophoresis) greatly enhances the permeation of
topical active ingredients across the stratum corneum.60
Gratieri et al61 demonstrated the increase in drug delivery of
transdermal iontophoretic administration of ketorolac in the mus-
cles of rats in vitro and in vivo, allowing shorter onset of action,
which is useful in managing localized pain and inflammation.
Conclusion
The benefits of topical pain formulations, compared with their
oral equivalents, include safety and efficacy in many cases. This
method of drug delivery can avoid or eliminate many of the
adverse effects that patients find problematic, sometimes to the
point of intolerance.
Topical preparations usually have minimal systemic effects,
such as gastrointestinal adverse effects, and also avoid first-
pass hepatic metabolism. Significant hypotension is a serious
adverse reaction with oral dosing of nifedipine, but topical
nifedipine is better tolerated.
Certain precautions are needed for topical and transdermal
preparations, too; however, and transdermal preparations
involve a greater systemic effect than topical preparations.
Topics in Pain Management
Extreme caution must be used when heated lidocaine/tetracaine
is used, as heat can increase the absorption of most drugs and
cardiac toxicity may be a potential adverse reaction with anes-
thetic agents. Systemic absorption of topical morphine is gen-
erally less than with oral administration, but topical morphine
has appeared in the urine of patients.
Pain practitioners should be aware of topical and transder-
mal options that might be appropriate for each patient, using
the evidence gathered in comparative studies with oral formu-
lations and compared with placeboand sometimes com-
pared with both. Such preparations may be available from
trusted compounding pharmacies and produced in various
forms, including creams, gels, ointments, patches, and sticks.
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1% ketamine in neuropathic pain syndromes: a randomized, double-
blind, placebo-controlled trial. Anesthesiology. 2005;103(1):140.
20. Boardman LA, Cooper AS, Blais LR, et al. Topical gabapentin in
the treatment of localized and generalized vulvodynia. Obstet
Gynecol. 2008;112(3):579.
21. Hiom S, Patel GK, Newcombe RG, et al. Severe postherpetic neu-
ralgia and other neuropathic pain syndromes alleviated by topical
gabapentin. Br J Dermatol. 2015;173(1):300-302.
22. Demant DT, Lund K, Finnerup NB, et al. Pain relief with lidocaine
5% patch in localized peripheral neuropathic pain in relation to pain
phenotype: a randomised, double-blind, and placebo-controlled,
phenotype panel study. Pain. 2015;156(11):2234-2244.
23. Devers A, Galer BS. Topical lidocaine patch relieves a variety of neuro-
pathic pain conditions: AN open label study. Clin J Pain. 2000;16(3):205.
24. Rowbotham MC, Davies PS, Fields HL. Topical lidocaine gel
relieves postherpetic neuralgia. Ann Neurol. 1995;37(2):246.
25. Gammaitoni A, Gallagher RM, Welz-Bosna M. Topical ketamine gel:
possible role in treating neuropathic pain. Pain Med. 2000;1(1):97.
26. Quan D, Wellish M, Gilden D. Topical ketamine treatment of post-
herpetic neuralgia. Neurology. 2003;60:1391-1392.
27. Wilken M, Ineck JR, Rule AM. Chronic arthritis pain management
with topical morphine: case series. J Pain Palliat Care Pharmacother.
2005;19(4):39-44.
28. Peppin JF, Albrecht PJ, Argoff C, et al. Skin matters: a review of
topical treatments for chronic pain. part two: treatments and appli-
cations. Pain Ther. 2015;4(1):33-50.
29. Niethard FU, Gold MS, Solomon GS, et al. Efficacy of topical
diclofenac diethylamine gel in osteoarthritis of the knee. J Rheumatol.
2005;32(12):2384-2392.
30. Radnovich R. Heated lidocaine-tetracaine patch for management of
shoulder impingement syndrome. J Am Osteopath Assoc. 2013;
113(1):58-64.
31. Radnovich R, Marriott TB. Utility of the heated lidocaine/tetracaine
patch in the treatment of pain associated with shoulder impingement
syndrome: a pilot study. Int J Gen Med. 2013;6:641-646.
7
Topics in Pain Management
32. Radnovich R, Trudeau J, Gammaitoni AR. A randomized clinical
study of the heated lidocaine/tetracaine patch versus subacromial
corticosteroid injection for the treatment of pain associated with
shoulder impingement syndrome. J Pain Res. 2014;7:727-735.
33. National Institute of Neurological Disorders and Stroke. National
Institutes of Health. Complex Regional Pain Syndrome Fact Sheet.
November 3, 2015. http://www.ninds.nih.gov/disorders/reflex_
sympathetic_dystrophy/detail_reflex_sympathetic_dystrophy.htm.
Accessed November 11, 2015.
34. Davis KD, Treede RD, Raja SN, et al. Topical application of cloni-
dine relieves hyperalgesia in patients with sympathetically main-
tained pain. Pain. 1991;47(3):309-317.
35. Kopsky D, Hesselink J. Multimodal stepped care approach involv-
ing topical analgesics for severe intractable neuropathic pain in
CRPS type 1: a case report. Case Rep Med. 2011;2011:319750.
36. Finch PM, Knudsen L, Drummond PD. Reduction of allodynia in
patients with complex regional pain syndrome: a double-blind placebo-
controlled trial of topical ketamine. Pain. 2009;146(1-2):18-25.
37. Ushida T, Tani T, Kanbara T, et al. Analgesic effects of ketamine
ointment in patients with complex regional pain syndrome type 1.
Reg Anesth Pain Med. 2002;27(5):524-528.
38. Gurtovenko AA, Anwar J. Modulating the structure and properties
of cell membranes: the molecular mechanism of action of dimethyl
sulfoxide. J Phys Chem B. 2007;111(35):10453-10460.
39. Zuurmond WW, Langendijk PN, Bezemer PD, et al. Treatment of
acute reflex sympathetic dystrophy with DMSO 50% in a fatty
cream. Acta Anaesthesiol Scand. 1996;40(3):364-367.
40. Geertzen JH, de Bruijn H, de Bruijn-Kofman AT, et al. Reflex
sympathetic dystrophy: early treatment and psychological aspects.
Arch Phys Med Rehabil. 1994;75(4):442-446.
41. Goris RJ, Dongen LM, Winters HA. Are toxic oxygen radicals
involved in the pathogenesis of reflex sympathetic dystrophy? Free
Radic Res Commun. 1987;3(1-5):13-18.
42. Anand P, Bley K. Topical capsaicin for pain management: therapeutic
potential and mechanisms of action of the new high-concentration
capsaicin 8% patch. Br J Anaesth. 2011;107(4):490-502.
43. Tandan R, Lewis GA, Krusinski PB, et al. Topical capsaicin in pain-
ful diabetic neuropathy. Controlled study with long-term follow-up.
Diab Care. 1992;15(1):8-14.
44. McCormack PL. Capsaicin dermal patch: in non-diabetic periph-
eral neuropathic pain. Drugs. 2010;70(14):1831-1842.
45. Heydari M, Homayouni K, Hashempur MH, et al. Topical citrullus
colocynthis (bitter apple) extract oil in painful diabetic neuropathy: a
double-blind randomized placebo-controlled clinical trial. J Diabetes.
2015. doi:10.1111/1753-0407.12287.
Coming Soon:
When do Lumbar Epidural Steroid Injections
Help? A Systematic Review, Part I and Part II
8 2016 Wolters Kluwer Health, Inc. All rights reserved.
February 2016
46. Somberg JC, Molnar J. Retrospective study on the analgesic activity
of a topical (TT-CTAC) cream in patients with diabetic neuropathy
and other chronic pain conditions. Am J Ther. 2015;22(3):214-221.
47. Yasam VR, Jakki SL, Natarajan J, et al. A novel vesicular transder-
mal delivery of nifedipinepreparation, characterization and in
vitro/in-vivo evaluation. Drug Deliv. 2015:1-12.
48. Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic acid and
diabetic neuropathy. Rev Diabet Stud. 2009;6(4):230-236.
49. Smith CR, Rodeheffer RJ. Treatment of Raynauds phenomenon
with calcium channel blockers. Am J Med. 1985;78(2B):39-42.
50. Pope JE. Drug Treatment of Raynauds Phenomenon. A Guide to
Pathogenesis and Treatment. New York: Springer; 2015:315-337.
51. Levien TL. Advances in the treatment of Raynauds phenomenon.
Vascu Health Risk Manag. 2010;6:167-177.
52. Dhawan S, Chopra S. Nonsurgical approaches for the treatment of
anal fissures. Am J Gastroenterol. 2007;102(6):1312-1321.
53. Aaolu N, Cengiz S, Arslan MK, et al. Oral nifedipine in the
treatment of chronic anal fissure. Dig Surg. 2003;20(5):452-456.
54. Ahmed HM. Comparative study of oral and topical nifedipine in the
treatment of chronic anal fissure. Sudanese J Public Health.
2010;5(4).
55. Carapeti E, Kamm M, Evans B, et al. Topical diltiazem and
bethanechol decrease anal sphincter pressure without side effects.
Gut. 1999;45(5):719-722.
56. Haefner HK, Collins ME, Davis GD, et al. The vulvodynia guide-
line. J Low Genit Tract Dis. 2005;9:40-51.
57. Hohmeier KC, Almon LM. Topical and intranasal analgesic ther-
apy in a woman with refractory postherpetic neuralgia. Case Rep
Med. 2015;2015:392874.
58. Sanz R, Calpena AC, Mallandrich M, et al. Enhancing topical
analgesic administration: review and prospect for transdermal and
transbuccal drug delivery systems. Curr Pharm Des. 2015;21(20):
2867-2882.
59. Al-Suwayeh SA, Taha EI, Al-Qahtani FM, et al. Evaluation of skin
permeation and analgesic activity effects of carbopol lornoxicam
topical gels containing penetration enhancer. Scientific World J.
2014;2014:127495.
60. Jorge LL, Feres CC, Teles VE. Topical preparations for pain relief:
efficacy and patient adherence. J Pain Res. 2011;4:11-24.
61. Gratieri T, Pujol-Bello E, Gelfuso GM, et al. Iontophoretic trans-
port kinetics of ketorolac in vitro and in vivo: demonstrating local
enhanced topical drug delivery to muscle. Eur J Pharm Biopharm.
2014;86(2):219-226.
Topics in Pain Management
CDC Issues Guidelines for Public Comment and Release Data
Showing Drug Overdose Deaths at Record Numbers for 2014
Anne Haddad
T he US Centers for Disease Control and Prevention (CDC)
published data December 18, 2015, that shows increases
in deaths related to drug overdose, including both prescription
and illicit street drugs, and continuing to call it an epidemic.
The most commonly prescribed opioid pain relieversnatu-
ral or semisynthetic opioids such as oxycodone and hydroco-
donecontinue to be involved in more overdose deaths than
any other opioid type, according to a press release on the
CDC website.1 These deaths increased by 9%, with 813 more
deaths in 2014 than in 2013.
Draft Guideline Issued and Up for Comment
Meanwhile, the agency also has published a draft guideline
on opioid prescribing, but many advocates for more responsi-
ble opioid prescribing remain concerned the guideline will
not be enough.
The guideline appeared in the December 14 Federal Register
and was to be open for comment until January 13. The recom-
mendations are for prescribing only in primary care settings
for patients with chronic pain lasting more than 3 months (and
which is not end-of-life care).
The CDCs National Center for Injury Prevention and
Controls Board of Scientific Counselors were scheduled to
create a working group in early January to review the com-
ments and make recommendations to the Board on revisions.
Authors of the guideline include Deborah Dowell, MD, and
Tamara Haegerich, PhD, from the CDCs Division of
Unintentional Injury Prevention, along with an outside expert,
Roger Chou, MD, from Oregon Health and Sciences University,
Portland.
Experts who reviewed it include representatives from the
Society of General Internal Medicine, American Academy of
Family Physicians, and American College of Physicians.
Data on Overdose Deaths
Data in the CDC report on overdose deaths published
December 18 in the agencys journal, Morbidity and Mortality
Weekly Report, include the following:
Between 2000 and 2014, nearly half a million Americans
died of drug overdoses.
Opioid overdose deaths, including both opioid pain reliev-
ers and heroin, hit record levels in 2014, with an alarming
14% increase in just 1 year.
Increases in prescription opioid pain reliever and heroin
deaths are the biggest driver of the drug overdose epidemic.
2016 Wolters Kluwer Health, Inc. All rights reserved.
February 2016
Deaths from heroin increased in 2014, continuing a sharp
rise that has seen heroin overdoses triple since 2010.
Deaths involving illicitly made fentanyl, a potent opioid
often added to or sold as heroin, are also on the upswing.
Drug overdose deaths are up in both men and women, in non-
Hispanic whites and blacks, and in adults of nearly all ages.
Rates of drug overdose deaths were highest among 5 states:
West Virginia, New Mexico, New Hampshire, Kentucky,
and Ohio. (See information below to find a map2 showing
deaths by state.)
The increasing number of deaths from opioid overdose is
alarming, said Tom Frieden, MD, MPH, director of the CDC.
The opioid epidemic is devastating American families and com-
munities. To curb these trends and save lives, we must help pre-
vent addiction and provide support and treatment to those who
suffer from opioid use disorders. This report also illustrates how
important it is that law enforcement intensify efforts to reduce the
availability of heroin, illegal fentanyl, and other illegal opioids.
Trends Driving Overdose Deaths
The findings indicate that 2 distinct but intertwined trends
of increases in both abused or misused legal drugs and illicit
drugs are driving overdose epidemic in the United States. The
study found:
1. A 15-year increase in deaths from prescription opioid pain
reliever overdoses as a result of misuse and abuse; and
2. A recent and continuing surge in illicit drug overdoses,
mainly involving heroin.
More than 6 in 10 drug overdose deaths in 2014 involved
opioids, including opioid pain relievers and heroin. The larg-
est increase in opioid overdose deaths involved synthetic opi-
oids (not including methadone), which were involved in 5500
deaths in 2014, nearly twice as many as the year before. Many
of these overdoses are believed to involve illicitly made fentanyl,
a short-acting opioid.
In addition, heroin-related death rates increased by 26%
from 2013 to 2014, totaling 10574 deaths in 2014.
Past misuse of prescription opioids is the strongest risk factor for
heroin initiation and useespecially among people who became
dependent upon or abused prescription opioids in the past year.
The increased availability of heroin, its relatively low price (com-
pared with prescription opioids), and high purity seem to be major
drivers of the upward trend in heroin use, overdoses, and deaths.
9
Topics in Pain Management
Efforts to Stop or Reverse the Trends
The new findings point to 4 ways to prevent overdose
deaths:
1. Limit initiation into opioid misuse and addiction. Opioid
pain reliever prescribing has quadrupled since 1999.
Providing health care professionals with additional tools
and informationincluding safer guidelines for prescrib-
ing these drugscan help them make more informed pre-
scribing decisions.
2. Expand access to evidence-based substance use disorder
treatmentincluding medication-assisted treatmentfor
people who suffer from opioid use disorder.
3. Protect people with opioid use disorder by expanding
access and use of naloxone. Naloxone can reverse the
symptoms of an opioid overdose and save lives. Some cit-
ies, such as Baltimore, have started programs to provide a
rescue dose of naloxone to the loved ones of those
addicted to heroin.
4. Coordinate an approach involving local health and law
enforcement agencies. State and local public health agencies,
medical examiners and coroners, and law enforcement
agencies must work together to improve detection of and
BESTFIT Studies Analyze Sleep Medications Role in Improving
Fibromyalgia Patient Outcomes
R esearchers presented data indicating that an investiga-
tional drug, a rapidly absorbed sublingual form of
cyclobenzaprine, when used as a sleep medication in patients
with fibromyalgia (FM), not only improved sleep, but also
improved patient outcomes related to pain and other measure-
ments.1-3
Disrupted and nonrestorative sleep is widely thought to play
a role in the pathophysiology of FM, suggesting that treat-
ments that improve sleep quality would address global symp-
toms that patients with FM experience.2
The BESTFIT (Bedtime Sublingual TNX-102 SL as
Fibromyalgia Intervention Therapy) study is a randomized, dou-
ble-blind, placebo-controlled trial of sublingual cycloben-
zaprine, called TNX-102 SL, in 205 participants who met the
2010 American College of Rheumatology (ACR) diagnostic cri-
teria for FM. The Phase 2b study was conducted at 17 US sites.1
The data are published in two abstracts in conjunction with
the November 2015 annual meeting of the ACR and the
Association of Rheumatology Health Professionals (ARHP).2,3
Nearly all of the authors in the study disclosed relationships
with Tonix Pharmaceuticals, which is developing the drug.
10
February 2016
response to illicit opioid overdose outbreaks to address
this emerging threat to public health and safety.
The CDC works with states, communities, and prescribers
to prevent opioid misuse and overdose by tracking and moni-
toring the epidemic and helping states scale up effective pro-
grams. The agency also seeks to improve patient safety by
equipping health care providers with data, tools, and guidance
so they can make informed treatment decisions.
According to the CDC, Sylvia Matthews Burwell, US secre-
tary of Health and Human Services, has made addressing opi-
oid abuse, dependence, and overdose a priority and work is
underway within HHS on this issue. Additional resources and
a link to the draft CDC Guideline for Prescribing Opioids for
Chronic Pain can be found at the CDCs home page on pre-
scription drug overdose: www.cdc.gov/drugoverdose.
References
1. CDC. Drug overdose deaths hit record numbers in 2014. http://
www.cdc.gov/media/releases/2015/p1218-drug-overdose.html.
2. CDC. A map of drug overdose deaths by state (2013 and 2014).
http://www.cdc.gov/drugoverdose/data/statedeaths.html.
3. CDC. Injury prevention and control: prescription drug overdose.
www.cdc.gov/drugoverdose.
TNX-102 SL is a proprietary eutectic sublingual tablet formu-
lation of low-dose (2.8 mg) cyclobenzaprine HCl. TNX-102
SL is an investigational new drug and has not been approved
for any indication.2
The sublingual tablet is designed for rapid absorption and
long-term, bedtime use.2,3 Participants in the study were
evenly randomized to receive either 1 tablet of sublingual
cyclobenzaprine (Bedtime TNX-102 SL) or placebo, and they
were instructed to take their study medication at bedtime for
12 weeks. The results from BESTFIT demonstrated that, at
week 12, TNX-102 SL significantly improved core symptoms
of FM as well as measures of the impact of this disorder on
patients daily lives.1
The authors concluded that the investigational drug
improved sleep quality by multiple measures in patients with
FM. They reported that the improvement in sleep quality was
followed by a period of improvement in FM measures includ-
ing pain and outcomes as measured by the Fibromyalgia
Impact Questionnaire-Revised (FIQ-R) and the Patient
Global Impression of Change (PGIC), which correlated with
(continued on page 12)
2016 Wolters Kluwer Health, Inc. All rights reserved.
Topics in Pain Management
Topics in Pain Management CME Quiz
To earn CME credit, you must read the CME article and
complete the quiz and evaluation assessment survey on the
enclosed form, answering at least 70% of the quiz questions
correctly. Select the best answer and use a blue or black pen
to completely fill in the corresponding box on the enclosed
answer form. Please indicate any name and address changes
directly on the answer form. If your name and address do not
appear on the answer form, please print that information in
the blank space at the top left of the page. Make a photocopy
of the completed answer form for your own files and mail the
original answer form in the enclosed postage-paid business
reply envelope. Your answer form must be received by
1. The incidence of gastrointestinal adverse effects is lower
with oral formulations than with topical formulations.
A. True
B. False
2. Which one of the following provides higher drug concen-
trations and significant systemic absorption?
A. Topical formulations
B. Transdermal formulations
3. Topical morphine used in the treatment of osteoarthritis
knee pain does not demonstrate systemic absorption.
A. True
B. False
4. Management of CRPS requires a trial-and-error approach.
A. True
B. False
5. Recent recommendations discourage the use of the high-
dose 8% capsaicin patch in patients with which of the fol-
lowing conditions?
A. Diabetic neuropathy
B. Nociceptive pain
C. Painful HIV-associated neuropathy
D. A and C
6. All the following are useful for treatment of anal fissures
and spasms, except
A. nifedipine
B. diltiazem 3%
C. albuterol
D. bethanechol 0.1%
2016 Wolters Kluwer Health, Inc. All rights reserved.
February 2016
Lippincott CME Institute by January 31, 2017. Only two
entries will be considered for credit.
Online quiz instructions: To take the quiz online, log on to
your account at www.topicsinpainmanagement.com, and
click on the CME tab at the top of the page. Then click on
Access the CME activity for this newsletter, which will
take you to the log-in page for http://cme.lww.com. Enter
your username and password. Follow the instructions on the
site. You may print your official certificate immediately.
Please note: Lippincott CME Institute, Inc., will not mail cer-
tificates to online participants. Online quizzes expire on the
due date.
7. Which one of the following is the mechanism of action of
nifedipine in the treatment of neuropathic pain?
A. Increasing circulation
B. Inhibitions of COX enzymes
C. Reducing blood glucose levels
8. The heated lidocaine/tetracaine patch is effective in treating
A. vulvodynia
B. Raynaud syndrome
C. anal fissures
D. bursitis
9. Which one of the following NSAIDs is frequently used
topically for OA-associated knee pain?
A. Diclofenac
B. Naproxen
C. Aspirin
D. Celecoxib
10. Iontophoresis and phonophoresis are some of the recent
technologies being investigated to enhance topical absorp-
tion of medications.
A True
B. False
11
Topics in Pain Management
(continued from page 10)
sleep quality improvements. Participants also were assessed
using the PROMIS Sleep Disturbance scale (PROMIS).2
The authors reported that this improvement is consistent
with the antagonistic activity of cyclobenzaprine at 5HT2A,
alpha-1 adrenergic, and H-1 receptors.
Together, these data suggest TNX-102 SL targets non-
restorative sleep and provides a novel approach to treating
FM, the authors wrote. 2
Subjects treated with TNX-102 SL improved in all measures
of sleep quality, as well as pain, FIQ-R, and PGIC ratings over
the 12-week study period. PROMIS sleep disturbance scale
scores reached statistical significance by week 4 and demon-
strated sustained benefit through week 12.
Daily sleep diary (change from baseline to endpoint)
reached statistical significance at week 1, regained signifi-
cance at week 6, and was sustained through week 12. The
sleep quality item on the FIQ-R reached significance at week
2 and was sustained through week 12.
Improvement in sleep based on PROMIS survey results cor-
related with improvement in pain by 30% responder analysis.
The authors reported that systemic adverse events were
infrequent, and that weight gain was negligible. About 42% of
treated patients reported transient tongue or sublingual numb-
ness at the sublingual administration site.
The investigational drug improved
sleep quality by multiple measures in
patients with fibromyalgia.
Additional Study Finds Responses for
Meaningful Effects Missed by Group Mean
Changes
In a poster session at the ACR/ARHP annual meeting, the
authors also presented a separately published study conclud-
ing that a Phase 2b trial of sublingual cyclobenzaprine/
Bedtime TNX-102 SL supports the finding that responder
analyses for analgesia and other patient-reported outcomes
may reveal significant and meaningful effects that are missed
by group mean changes.3
The authors reported that in the particular case of the
BESTFIT study of TNX-102 SL, the pain questionnaire was
not specific to central or regional pain, and TNX-102 SL targets
non-restorative sleep with secondary improvement in pain.3
Clinical studies that rely on patient self-reported outcome
measures such as pain scales may be analyzed by responder
analysis (comparisons of proportions of treated patients
achieving a predefined clinically meaningful improvement
threshold) and by group mean changes. In a Phase 2b trial of
12
February 2016
TNX-102 SL1 in FM patients (BESTFIT), we compared
these approaches to the evaluation of changes in pain and FM
symptoms, the authors wrote.3
For this analysis, we compared changes in pain score, patient
global impression of change (PGIC), and Fibromyalgia Impact
Questionnaire-Revised (FIQ-R), analyzed by both responder
analyses and group mean change from baseline techniques,
they wrote.3
Specifically, they reported:
For the daily pain diary, the responder analysis resulted in
34.0% on TNX-102 SL compared with 20.6% on placebo.
The same daily pain data, when analyzed as mean change
from baseline, demonstrated that TNX-102 SL had
improvement of 1.50 units vs. 1.0 units on placebo.
Using the FIQ-R pain item as the pain measure resulted in
a response rate of 38.8% on TNX-102 SL vs. 23.5% on
placebo, while the mean change was 1.8 on TNX-102 SL
vs 0.7 on placebo.
PGIC is a 7-point Likert scale and defining response very
much improved or much improved. The response rate
was 30.1% on TNX-102 SL vs. 16.7% on placebo, and the
mean change was 3.1 on TNX-102 SL vs 3.6 on placebo.
FIQ-R was evaluated as 21 discrete items, 3 defined
domains (symptoms, overall impact, and function) and a
total score. The FIQ-R total score and symptom domain
differed statistically between treatment groups by both
responder and mean analyses. The function domain sepa-
rated on the responder analysis but was not significant (P =
0.059) on mean change.3
An ongoing confirmatory study is using pain and other
responder analyses as the primary and secondary endpoints,
which are more appropriate and sensitive measures for the
evaluation of TNX-102 SL for FM.3
References
1. Tonix Pharmaceuticals. Research & development: TNX-102 SL
for fibromyalgia. http://www.tonixpharma.com/research-development/
tnx-102-sl-for-fibromyalgia.
2. Moldofsky H, Gendreau RM, Clauw DJ, et al. Relationship of sleep
quality and fibromyalgia outcomes in a Phase 2b randomized, dou-
ble-blind, placebo-controlled study of bedtime, rapidly absorbed,
sublingual cyclobenzaprine (TNX-102 SL) [abstract]. Arth Rheumatol.
2015; 67 (suppl 10). http://acrabstracts.org/abstract/relationship-of-
sleep-quality-and-fibromyalgia-outcomes-in-a-Phase-2b-ran
domized-double-blind-placebo-controlled-study-of-bedtime-rapidly-
absorbed-sublingual-cyclobenzaprine-tnx-102-sl.
3. Gendreau RM, Clauw DJ, Gendreau J, et al. Responder compared
to mean change analyses in a fibromyalgia Phase 2b clinical study
of bedtime rapidly absorbed sublingual cyclobenzaprine (TNX-
102 SL) [abstract]. Arth Rheumatol. 2015; 67 (suppl 10). http://
acrabstracts.org/abstract/responder-compared-to-mean-change-
analyses-in-a-fibromyalgia-Phase-2b-clinical-study-of-bedtime-
rapidly-absorbed-sublingual-cyclobenzaprine-tnx-102-sl.
2016 Wolters Kluwer Health, Inc. All rights reserved.