Tag Archive: pain-treatment

Research on the association of vitamin D status with pain conditions continues to accumulate. In this latest study, a multinational European group of researchers found in a large sample of men that having musculoskeletal pain, particularly chronic widespread pain, was significantly influenced by low levels of vitamin D.

As part of the extensive European Male Ageing Study (EMAS), men 40 to 79 years of age completed a mailed pain assessment questionnaire and attended a clinical assessment that included measurement of vitamin D status signified by 25-hydroxyvitamin D3, or 25(OH)D, levels [McBeth et al. 2010]. Subjects were classified according to 25(OH)D levels as “normal” (≥15 ng/ml) or “low” (<15 ng/ml). Of 3,075 male participants included in the analysis (mean age 60 years, primarily Caucasian), 1,262 (41.0%) were pain-free, 1,550 (50.4%) reported “other pain” that did not satisfy criteria for chronic widespread pain (CWP), and 263 (8.6%) reported CWP. Compared with patients who were pain-free, those with “other pain” and those with CWP had significantly lower 25(OH)D levels (p<0.05).

After adjusting for age, men having “other pain” were 30% more likely to have low 25(OH)D, and having CWP was associated with a 50% greater likelihood of low 25(OH)D. These relationships persisted after adjusting for physical activity levels as a surrogate marker for sunshine exposure; however, after adjusting for additional lifestyle factors (such as smoking and alcohol use) the relationship of pain and low 25(OH)D was somewhat decreased — although, those with low vitamin D levels were still 20% more likely to also have pain.

COMMENTARY: In this large study, “other pain” was defined as any pain lasting one day or more in the past month and CWP was based on established criteria for diagnosing fibromyalgia. The total sample mean 25(OH)D level was 25 ng/mL, which could be considered overall as somewhat inadequate, and using a cut-off level of 15 ng/mL to separate “normal” versus “low” values is unusual, since many of those classified as normal still would have deficient levels (<20 ng/mL). It is interesting to note that the significant prevalence of CWP in this population of men was fairly equally distributed across 25(OH)D levels extending from <10 ng/mL to 30+ ng/mL. This suggests that there is a wide range of vitamin D deficiency and insufficiency that might influence CWP, including higher levels that many would otherwise consider as quite adequate 25(OH)D (ie, >30 ng/mL).

In the study population, men who were depressed, smoked cigarettes, and/or reported more frequent alcohol use were more likely to have low 25(OH)D levels. We have previously reported on the negative effects of tobacco and alcohol on 25(OH)D status in our review of vitamin D and pain [see PDF of paper here, page 25]. The investigators also examined levels of serum calcium and parathyroid hormone and found no significant differences between men with or without pain; therefore, clinically evident osteomalacia due to insufficient vitamin D may not have been a major influence (however, there also can be subclinical manifestations of difficult-to-detect osteomalacia).

Of further interest, an earlier published study, from the UK, similarly examined a large but mixed-gender population with and without CWP [reported in our blogpost 8/1/09]. In this study, 11% of men and 12.5% of women had CWP; however, an association of low 25(OH)D levels and pain was found in the women but not the men, and this was not accounted for by differences in lifestyle, anxiety, depression, or diet (although, persons with either high or low body mass index were more adversely affected by deficient vitamin D status). The present study, covering a larger and more diverse European population of men, supports the likelihood that CWP may be equally influenced by vitamin D status in both men and women.

As usual, however, we must caution that cross-sectional studies such as these from Europe and the UK do not confirm a direct cause-effect relationship between pain and low vitamin D status, and there appear to be certain potentially confounding factors. Furthermore, none of the researchers reported on clinical outcomes achieved via vitamin D supplementation in their subjects with pain, and this is a common shortcoming of much research in this field of inquiry that needs to be corrected.

REFERENCE: McBeth J, Pye SR, O’Neill TW, et al. Musculoskeletal pain is associated with very low levels of vitamin D in men: results from the European Male Ageing Study. Ann Rheum Dis. 2010;69:1448-1452 [abstract here].

According to an evidence review from Pain Treatment Topics, opioid antagonists like
naloxone and naltrexone — which block opioid drugs from activating their receptors — may
be surprisingly helpful for relieving difficult-to-treat pain conditions.
Glenview, IL; March 2009 – Achieving effective, durable, and safe pain relief, especially in
patients with chronic and/or severe pain conditions, can be difficult. For many types of pain,
prescription opioids are among the most effective analgesics. Yet, there is a growing body of
evidence suggesting potential benefits of opioid antagonists, particularly naloxone and

This is somewhat unexpected because these drugs displace opioid molecules from
their neuroreceptors, and block opioids from attaching to and activating those receptors.
In a peer-reviewed, evidence-based report for Pain Treatment Topics (http://Pain-Topics.org)
editor Stewart B. Leavitt, MA, PhD, describes naloxone and naltrexone pharmacology and the
theoretical foundations of opioid antagonists for pain management. Titled “Opioid Antagonists,
Naloxone & Naltrexone — Aids for Pain Management,” the 16-page report includes summaries
of 17 studies — case examples and clinical trials – investigating opioid-antagonist therapy in adult
humans. The complete report with references can be freely accessed at the Pain-Topics.org
website at <http://pain-topics.org/clinical_concepts/innovations.php&gt;.

Naloxone and naltrexone have been extensively studied in the past, and are FDA-approved for
the treatment of alcoholism or opioid addiction (naltrexone) or opioid overdose (naloxone). A
long-acting form of naltrexone for intramuscular injection also is approved for addiction therapy.
These antagonists also are being used or tested as ingredients in specially formulated opioid
analgesics to deter their misuse or abuse.

Leavitt notes, however, “doses of naloxone or naltrexone used in pain management are generally
much smaller than in other applications; either in the 1 to 5 mg range, referred to as ‘low dose,’ or
less than 1 mg, in microgram amounts, designated as ‘ultralow dose.’ In animal studies and
human trials, low- or ultralow-doses of antagonists appear to enhance the pain-relieving efficacy
of opioid-agonist analgesics, such as morphine, oxycodone, and others. Along with this, tolerance
to and physiologic dependency on opioid analgesics, as well as certain opioid side effects, may

PressRelease-16 be diminished. Furthermore, low-dose naltrexone has been successfully tested by itself as
monotherapy for the management of several pain-related conditions, including Crohn’s disease,
irritable bowel syndrome, and fibromyalgia.”

Explanatory mechanisms of action behind the benefits of opioid antagonists in pain management
are still under investigation. Essentially, appropriately low doses of opioid antagonists have been
postulated to “reset” the opioid-receptor system for a period of time, which seems analogous to
how rebooting a malfunctioning computer clears memory, refreshes the software, and often
restores normal function. With opioid-agonist therapy, the body becomes better attuned to the
beneficial effects of both external opioids, such as morphine, and naturally occurring internal
opioids, such as endorphins.

Clinical research to date on low- or ultralow dose applications of opioid antagonists for pain
management in humans has been limited. Still, the available evidence described in this report
suggests a number of possibilities that may be of interest to healthcare providers and their
patients with pain, including:
Brief detoxification using naloxone for difficult cases of opioid-unresponsive intractable
pain, opioid tolerance, or suspected opioid-induced hyperalgesia.

Ultralow-dose naloxone combined with various opioid agonists for managing
postoperative pain.

Ultralow-dose naltrexone (oral) or naloxone (intrathecal) as a component of intrathecal
opioid analgesia for difficult cases of intractable pain.

Ultralow-dose oral naltrexone combined with opioid agonists to provide an opioid-sparing
effect, offering equivalent pain relief at lower opioid doses.

Oral ultra-low dose naloxone or naltrexone combined with oral opioid analgesics to help
prevent or reverse opioid-induced constipation and to potentially reduce other opioid side

Ultralow-dose naltrexone to help facilitate more comfortable opioid-agonist tapering.
Low-dose naltrexone monotherapy for Crohn’s disease, and possibly for fibromyalgia and
short-term treatment of irritable bowel syndrome.

“Although further investigations to assess the safety and efficacy of these applications would be
appropriate,” Leavitt suggests, “both of these agents have passed animal and clinical toxicity
studies, and have been used for years in applications other than those described in this research
report. Therefore, it is not surprising that they have exhibited favorable safety profiles when
applied at low- and ultralow-dose levels, with few notices of adverse events or side effects at
these doses when used individually as monotherapy or in combination with opioid analgesics.”
“Naloxone and naltrexone are available today as generic, economically priced drugs, and it is
important that practitioners become aware of the therapeutic options that these may provide for
patient care,” Leavitt concludes. “However, it must be understood that opioid antagonists are not
yet FDA-approved for pain management purposes, so low- or ultralow-dose naloxone or
naltrexone would need to be cautiously prescribed off-label for compounding at properly equipped
*** NOTE: The contents of this report are for educational purposes and are not intended to
endorse or promote the off-label prescribing of any drugs. Practitioners are advised to study the
available evidence and use professional discretion in their prescribing decisions.

Pain Treatment Topics and the associated Pain-Topics.org website provide open and free
access to noncommercial, evidence-based clinical news, information, research, and education on
the causes and effective treatment of the many types of pain conditions. The project is
independently produced and currently supported by educational grants from Purdue Pharma L.P.,
Stamford, Connecticut, and Covidien/Mallinckrodt Inc., St. Louis, MO, leading manufacturers of
opioid analgesic products. The sponsors had no participatory role in the initiation or development
of this report on opioid antagonists in pain management.

Pain Therapeutics, Inc. (Nasdaq: PTIE) today announced the initiation of a Phase III study with Oxytrex, an investigational drug. Oxytrex is a unique oral painkiller for patients who suffer from persistent severe chronic pain. The Company believes Oxytrex offers less physical dependence/withdrawal than oxycodone, an 80-year-old prescription painkiller still widely used today to treat persistent severe chronic pain.

„We remain encouraged by the strong science around Oxytrex published in several top journals, including a recent article in Journal of Neurobiology that further elucidates the unique attributes of ultra-low-dose opioid antagonists,“ said Remi Barbier, president and chief executive officer.

This study is being referred to as the „Extreme Study“ in deference to patients who depend on extremely high daily doses of oxycodone (greater than or equal to 120 mg per day) to treat severe chronic pain. The Company believes this sub-population of patients is prone to physical dependence/withdrawal.

In the second half of 2007, Pain Therapeutics plans to initiate a large study with Oxytrex in a broad patient population.

„Extreme Study“ Design

This clinical study is randomized, double-blinded, multi-center and placebo-controlled. The study will enroll approximately 120 patients who have each been taking greater than or equal to 120 mg of oxycodone per patient per day for over a year. Patients who meet this and all other eligibility requirements are randomized to receive twice-daily doses of 100 nanograms (i.e., 0.0001 mg) ultra-low-dose naltrexone or matching placebo for two weeks. At the conclusion of the treatment period, patients check into a clinic and receive an injection of a high-dose opioid antagonist to precipitate withdrawal. During the withdrawal phase of the study, patients are closely monitored and measured for signs and symptoms of physical dependence/withdrawal using the Subjective Opiate Withdrawal Scale. The study’s primary endpoint is prospectively defined as physical dependence/withdrawal scores in the treated arm compared to placebo. For ethical and other reasons, the study protocol allows an interim analysis.

About Oxytrex

Pain Therapeutics owns commercial rights to Oxytrex, a unique oral painkiller that preferentially inhibits an excitatory effect of opioid receptors. This excitatory effect is believed to counteract analgesia (pain relief) and cause tolerance. Its inhibition enhances pain relief and minimizes opioid tolerance. The FDA has not yet evaluated the merits, safety or efficacy of Oxytrex.


Oxytrex (Pain Therapeutics, Inc.) is an oral opioid that combines a therapeutic amount of oxycodone with an ultra-low dose of the antagonist naltrexone. Animal data indicate that this combination minimizes the development of physical dependence and analgesic tolerance while prolonging analgesia. Oxytrex is in late-stage clinical development by Pain Therapeutics for the treatment of moderate-to-severe chronic pain. To evaluate the safety and efficacy of the oxycodone/naltrexone combination, three clinical studies have been conducted, one in healthy volunteers and the other two in patients with chronic pain. The putative mechanism of ultra-low-dose naltrexone is to prevent an alteration in G-protein coupling by opioid receptors that is associated with opioid tolerance and dependence. Opioid agonists are initially inhibitory but become excitatory through constant opioid receptor activity. The agonist/antagonist combination of Oxytrex may reduce the conversion from an inhibitory to an excitatory receptor, thereby decreasing the development of tolerance and physical dependence.

PMID: 17685875 [PubMed – indexed for MEDLINE]

Achieving effective, durable, and safe pain relief, especially
in patients with chronic and/or severe pain conditions,
can be a clinical challenge. For many types of pain, prescription
opioids are among the most effective analgesics [Fine
and Portenoy 2004]. However, there could be concerns about the
development of opioid tolerance or adverse effects, and in some
cases opioids seem to worsen pain (eg, hyperalgesia) [Compton
2008; DuPen et al. 2007; Stein et al. 2003]. For certain difficult
conditions, such as fibromyalgia or neuropathies, opioids alone are
sometimes considered of limited effectiveness [Chou et al. 2009].
Healthcare providers interested in pain management must be
alert to new or novel approaches that help to overcome deficiencies
of opioids, such as treatment-limiting side effects, and as aids
in relieving difficult-to-treat pain conditions. In this regard, there is
a growing body of evidence suggesting potential benefits of opioid
Opioid antagonists — in particular, naloxone and naltrexone —
have been available and studied for decades as agents that displace
opioid molecules from their neuroreceptors, and block
opioids from attaching to and activating those receptors. Such
qualities can be of important benefit, as short-acting antagonists
like naloxone are used effectively to quickly reverse toxic effects of
opioid overmedication or overdose.
Laboratory research and clinical trials have demonstrated the
unexpected, paradoxical effects of opioid antagonists as adjuvants
for enhancing rather than attenuating analgesic effects of opioids
like morphine, oxycodone, and others. Further benefits of opioid
antagonists, as monotherapy, for better managing certain chronic
pain conditions also have been discovered.


Pain and addiction share some common physiologic pathways
in the brain, especially those involving opioids, and each may
affect the other. That is, the presence of pain may influence the
development and course of opioid addiction, and vice versa
(Compton and Gebhart 2003).
These interactions may complicate therapy for opioid addiction.
For example, opioid-addicted persons appear to have lower tolerance
for and greater sensitivity to pain, and this may continue during
addiction treatment. Sleep disorders and psychiatric illness often
associated with addiction may increase the experience of pain
and decrease the effectiveness of pain-relief interventions. Furthermore, opioid medications
may lose their analgesic potency in many of these patients, so the management of their pain
can be challenging (Compton and Gebhart 2003).

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