Opioid and Nonopioid Therapies for the Management of Pain

[Guest guest]

Opioid and Nonopioid Therapies for the Management of Pain

http://www.abkhazia.com/content/view/1088/74/

Written by Ramaz Mitaishvili

Lynn R. Webster, MD, FACPM, FASAM

Introduction

The evolving need of pain patients for safe, effective analgesia is

driving research into new therapeutic modalities and fresh

approaches to familiar treatments. Innovation, involving both opioid

and nonopioid pain therapies, dominated discussion at the 23rd

Annual Meeting of the American Academy of Pain Medicine held

February 7-10 in New Orleans, Louisiana. Because some patients fail

to achieve a good outcome with opioid therapy, nonopioid medications

and interventions are receiving greater research attention. Opioids

are also the subject of new exploration, most of this directed

toward separating desired analgesia from unwanted side effects such

as euphoria, tolerance, abuse risk, and constipation.

Pros and Cons of Systemic Opioids

A debate titled " Opioids: Good or Bad? " posed a seemingly simple

question, then proceeded to prove the answer is most complex.[1] It

was suggested that the downside of opioids -- including opioid-

induced hyperalgesia,[2,3] hormonal suppression, and problems with

self-administration -- could be attenuated by switching to

interventional therapies such as implantable pumps to administer

analgesia.

A contrasting view presented during the debate is that systemically-

delivered opioids provide safe, effective analgesia with a far lower

risk for adverse events than many other medications, including

nonsteroidal anti-inflammatory drugs.[1] However, it was emphasized

that effective opioid therapy requires careful patient selection,

assessment, and monitoring, including a willingness to change course

when multiple titrations and rotations achieve no clear benefit.[1]

Nonopioid Alternatives

Cannabinoids

Cannabinoids have demonstrated significant analgesic properties, but

problems with side effects remain. Newer compounds show promise for

analgesic efficacy while reducing common side effects of dizziness,

euphoria, fatigue, and nausea.[4]

An oral mucosal spray (Sativex, GW Pharmaceuticals) that contains

2.7 mg of delta-9-tetrahydrocannabinol (THC) and 2.5 mg of

cannabidiol (CBD) has been well tolerated in clinical studies. The

co-administration of CBD appears to reduce the psychoactive effects

of THC, and intoxication is less than with oral THC, according to

presenters at AAPM.[4] Patients are allowed to self-titrate,

resulting in an average dose of approximately 20-30 mg/day of both

THC and CBD.[5] A double-blind, randomized, placebo-controlled study

of 160 outpatients with multiple sclerosis (MS) reported significant

reduction of spasticity with the cannabis-based medicinal extract

(CBME) (Sativex) compared to placebo (P = .001).[6] A pooled

analysis across 3 phase 3 MS spasticity studies, incorporating 666

patients, showed that CBME oral mucosal spray was significantly

superior to placebo (P < .05).

The CBME compound has been approved in Canada to treat neuropathic

pain generated by MS. Several US clinical trials have been

performed, and the US Food and Drug Administration has approved

phase 3 studies to evaluate CBME oral mucosal spray in patients with

cancer. Obstacles remain to achieving full regulatory and legal

approval for cannabis-based medicine in the United States. Eleven

states have medical marijuana laws providing patients and caregivers

a defense against prosecution; however, federal rulings have created

gray areas in how far a practitioner may go to help a patient obtain

cannabis.

Spinal Cord Stimulation

Two abstracts emphasized the selective targeting of stimulation

sites in therapies utilizing spinal cord stimulation (SCS).

The findings of a prospective, multicenter study support SCS as

effective for axial low back pain. Outcome data for 159 subjects who

received permanent implants showed significant pain improvement at

3.5 months and at 6- and 12-month evaluation time points (P < .001).

[7]

The selective stimulation of sacral nerves proved effective in

relieving the pain of 2 women, both of whom had suffered long-time

pudendal neuropathy and whose treatment options had been exhausted.

[8] The 2 subjects underwent bilateral S3 lead implantation. Both

patients achieved excellent relief thereby suggesting that SCS may

be an effective option for some patients with pudendal neuropathy.

Targeting Transient Receptor Potential Vanilloid Receptor (TRPV)1

Receptors

Transient receptor potential vanilloid-1 (TRPV1) receptors act as a

transducer for heat and low pH (protons).[9] These receptors are

plentiful in the skin where they can be activated by trauma and

contribute to postoperative pain. Investigational drug 4975 is a

long-acting nonopioid analgesic that targets TRPV1 receptors. The

drug was shown to be effective for postoperative pain when

administered in a single intra-operative dose as part of a

multimodal analgesic protocol. Fifty patients who underwent total

knee arthroplasty were randomized to receive a single administration

of 60 mL of 4975 or placebo along with concomitant preoperative,

intraoperative, and postoperative analgesics.[10] The 4975 group

reported significantly less pain on first ambulation at day 1 (5.4

vs 7.1 Brief Pain Inventory score) (P = .027) with analgesic

benefits at 2 weeks after surgery.

Innovations in Opioid Therapy

Nonselective Opioid Antagonists/Partial Agonists

Fakata and colleagues[11] presented a class review of peripherally

acting opioid antagonists. Administered in combination with mu-

receptor agonists, opioid antagonists appear to confer benefits for

abuse deterrence and analgesia. Some evidence indicates that opioid-

induced tolerance and hyperalgesia could be at least partially

blocked by the administration of an ultra-low-dose antagonist in

combination with mu-receptor agonist therapy.[12] Other

agonist/antagonist combinations contain a sustained-release opioid

with a sequestered antagonist, such as naltrexone. The antagonist is

only released when the product is crushed, damaged, dissolved, mixed

with alcohol or water, or otherwise manipulated in an attempt to

extract an abusable portion of active ingredient.[13] Taken as

directed, the sustained-release action of the opioid remains intact.

Although addicted people may still find clever ways to release an

abusable portion of opioid, abuse-deterrent formulations may stop

some abuse, prevent some overdose deaths, and increase primary-care

confidence in opioid prescribing.

Another formulation discussed in the review addresses lack of

analgesic efficacy.[11] Patients who fail to achieve lasting

analgesia with long-term opioid therapy have achieved benefit using

sublingual buprenorphine, a partial mu agonist. The drug was

investigated in an open-label study with 95 consecutive patients who

were referred by local pain clinics for detoxification from long-

term opiate analgesic therapy (mean 8.8 years) due to increasing

pain levels, worsening function and -- in 8% -- opiate addiction.

[14] After abstaining from all opiate analgesics for a minimum of 12

hours, patients received low doses of sublingual buprenorphine or

buprenorphine/naloxone. The daily sublingual buprenorphine dose

ranged from 4 to 16 mg (mean, 8 mg) for an average duration of 8.8

months. Eighty-six percent of patients experienced moderate-to-

substantial pain relief, improved mood, and functioning.

Sublingual buprenorphine is approved for opioid detoxification in

patients with a primary opioid addiction. Physicians who use

buprenorphine for opioid detoxification must be awarded a special

license from the US Drug Enforcement Agency.

Peripheral Opioid Antagonists to Reduce Side Effects

Fakata and colleagues[11] also discussed peripheral opioid

antagonists designed to reduce side effects. Peripheral effects of

opioids include inhibition of small intestine motility, the

inhibition of normal colonic movements, and delayed transit,

resulting in opioid-induced constipation. Opioid-induced

constipation reduces quality of life, increases pain severity, and

impairs activities, including work. Two new medications utilize a

peripherally acting opioid receptor antagonist that does not cross

the blood-brain barrier but directly targets the mechanism of bowel

dysfunction to reverse an opioid's effects.

Two phase 3, randomized, double-blind, placebo-controlled trials

that enrolled 154 and 133 patients, respectively, showed that

subcutaneous methylnaltrexone improved laxation (62% in the first

study; 48.4% in the second study) within the first 4 hours of drug

administration with no significant changes in pain scores.[15]

Median time to laxation was significantly greater (P < .0001) at

0.15 mg/kg (70 minutes in the first study) and 0.30 mg/kg (45

minutes in the second study) compared with placebo (less than 24

hours).

Alvimopan is another peripheral mu antagonist shown to increase

gastrointestinal motility and to reduce opioid effects on the gut

while demonstrating low systemic absorption. A meta-analysis of 5

randomized-controlled trials compared alvimopan with placebo

following bowel resection or hysterectomy.[16] Data were reported on

2195 patients: a total of 1521 (69.3%) received alvimopan and 674

(30.7%) received placebo. The primary efficacy endpoint measures --

passage of flatus, stool, and tolerance of solid food --

significantly improved with alvimopan as did time to discharge after

major surgery.

Side effects of both medications are similar to those of common

laxatives and include abdominal cramping, diarrhea, nausea, and

flatulence.

Metabolism of Opioids

Metabolism of opioids is influenced by individual genetic

variability, a reality that could have implications for the

selection and monitoring of pain therapies. Because opioids are

metabolized by polymorphic enzymes, including CYP2D6, researchers

from the Medical College of Wisconsin undertook a study to evaluate

the clinical efficacy of CYP2D6 genotyping for chronic pain patients

on analgesic therapy.[17]

Patients were classified as extensive metabolizers, intermediate

metabolizers, and poor metabolizers by measuring steady-state opioid

concentrations using liquid chromatography/mass spectrometry/mass

spectrometry. The higher the steady-state concentrations, the

greater the opportunity for adverse drug reactions, according to

study investigators. As hypothesized, patients classed as poor

metabolizers (5% of the sample) had the highest steady-state opioid

concentrations. Of the patients who reported adverse drug reactions,

80% also had impaired CYP2D6 metabolism.

Pharmacogenetic analysis may become more routine to facilitate the

selection of treatments and to predict and monitor disease. Genetic

profiling also may present ethical issues for purposes of insuring

or hiring the individual. These issues have yet to be fully defined

and addressed.

Conclusion

Pain medicine will continue to evolve as time and research clarify

the risks and benefits of long-term opioid therapy for chronic

nonmalignant pain. Heightened patient selection, monitoring

measures, and treatment adjustments may increase chances for

beneficial outcomes with opioid therapy. Novel opioid formulations,

including some that utilize opioid antagonists, may prove valuable

for mitigating some opioid-induced side effects. Some patients with

pain resistant to systemic opioids or with dose-limiting side

effects may require a different route of administration or a

nonopioid alternative. Research into cannabinoids as a nonopioid

class of analgesia appears promising, but legal and regulatory

hurdles remain to the approval of cannabis-derived medicines for

pain treatment. Pain treatments and clinical investigations are

likely to continue in the direction of nontraditional opioid and

nonopioid therapies.

Supported by an independent educational grant from Cephalon

[Guest guest]

When our son was living in Vancouver, BC, my husband went to an MS doctor at UBC

and got a prescription for Sativex. It didn't really help that much, was very

expensive, and tasted awful. It could be that he didn't titrate himself to a

high enough amount. His attitude as observed from the outside seems to be best

on his current regime of Provigil and EffexorXR.

Elinor