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Approximately 2-5% of the world population has been diagnosed with fibromyalgia (FM) with more women than men affected. Fibromyalgia most commonly presents as a general pain-all-over, typically affecting the body bilaterally both above and below the waist. Pain on presentation is usually severe, poorly localized, and debilitating. Additionally, pain associated with FM exhibits increased sensitivity, or hyperalgesia.

Fibromyalgia is a conglomerate of many pain disorders, which makes diagnosis and treatment quite difficult. Inflammatory cytokines that are known to promote nociception, allodynia, and hyperalgesia in FM include TNFa and interleukins (1(12,6,15, 17). Parkinty and Younger22 showed a reduction in serum concentrations of TNFa and interleukins during a 10-week, single-blinded, crossover trial investigating the effect of 4.5 mg naltrexone on serum markers of inflammation in eight women with fibromyalgia.

The most successful FDA-approved treatment options for FM have focused on afferent pain pathways. Drugs that affect the afferent pain pathways include antidepressants that modulate serotonin and/or norepinephrine (e.g., amitriptyline, duloxetine, milnacipran) and anticonvulsants acting as ligands of alpha-2-delta voltage-gated calcium channels in the CNS (e.g., gabapentin, pregabalin). It is important to note that FM is not effectively treated with opioid analgesics. Alternatively, opioids have been associated with opioid-induced hyperalgesia in the context of FM. Antidepressant and anticonvulsant medications manage the symptomatology of inflammation and immune dysfunction in FM, but do not directly affect the underlying pathology. As stated above, LDN has been shown to decrease the serum concentrations of immune and inflammatory cytokines, thus addressing FM pain from a more direct pathologic approach.22

A study in ten women with fibromyalgia who were administered 4.5 mg LDN daily for 8 weeks found that LDN reduced fibromyalgia symptoms for all study patients with a >30% improvement over placebo as measured by daily reports of symptom severity and tests. Twice monthly tests of mechanical, heat, and cold pain sensitivity demonstrated that mechanical and heat pain thresholds were improved with the drug. Patients with higher erythrocyte sedimentation rates had the greatest reduction in symptoms with LDN.23

A larger study in 31 women with fibromyalgia evaluated LDN 4.5 mg daily for a period of 12 weeks with 4 weeks of placebo taken either before or after the LDN treatment period depending on study arm assignment. This study also included a 2-week baseline period and a 4-week follow-up period for a total length of 22 weeks. All participants were told that they had the option to reduce their daily dosage to 3 mg if they experienced side effects. Self-assessed pain, fatigue, and other symptoms were recorded on a daily basis during the study and for 4 weeks after study medication was stopped. Twenty-eight women had sufficient data to be included in the analyses. Study patients experienced a significantly greater reduction in their pain scores while they were taking the LDN as compared with placebo (28.8% reduction versus 18.0% reduction; p=0.016). More participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during LDN therapy compared to placebo (32% response during LDN versus 11% response during placebo; p=0.05). Participants also reported improved general satisfaction with life and improved mood while taking LDN. However, there was no improvement in fatigue or sleep. Four individuals (three while taking LDN and one while taking placebo) requested the 3 mg dosage due to side effects (headaches, heartburn, and irritability). These side effects were reduced by lowering the dosage to 3 mg/day.24

Pain, Complex Regional Pain Syndrome, and Diabetic Neuropathy

According to the Centers for Disease Control and Prevention (2017), the sales of prescription opioids increased 400% between 1999 and 2014, but the incidence of pain in the U.S. did not change during that same period.25 Notwithstanding, more than 100 million people in the U.S. live with chronic pain conditions. It is imperative, now more than ever, to find treatment options that are not only effective, but also safe for patients.

Pain is a very complex disease that is affected by both neural and immune systems in the peripheral nervous system (PNS) and CNS. It is categorized as either adaptive pain, immunologic pain, and/or maladaptive pain.

Adaptive pain is a result of tissue damage either from trauma or surgery and is propagated through the processes of transduction, conduction, transmission, perception, and modulation. Transduction involves the release of cytokines and chemokines from nociceptors in the somatic and visceral structures activated by mechanical, thermal, or chemical stimuli. Conduction involves the generation of action potentials by the depolarization of voltage-gated sodium channels. Transmission through afferent nerve fibers causes the release of glutamate and substance P acting as excitatory neurotransmitters, ultimately propagating the pain signal to the thalamus, where the signal is relayed to higher cortical structures. Perception is the result of the pain signals that reach the higher cortical structures becoming a conscious experience. Modulation is the result of many different neurotransmitters and receptor interactions that either strengthen or attenuate the pain signal. Excitatory neurotransmitters involved in pain include glutamate and substance P. Inhibitory neurotransmitters involved in pain include enkephalins, (3-endorphins, GABA, norepinephrine, and serotonin. Additionally, NMDA receptors seem to influence opioid receptor responsiveness to exogenous and endogenous opioids.

The interaction between the immune system and pain has become an accepted theory in pain experience and management. It is believed that microglial cells in the CNS are activated following nerve injury, which is often seen in neuropathic pain conditions. Additionally, activation of microglia may play a role in tolerance to opioids as well as opioid-induced hyperalgesia.

Maladaptive pain is the result of damage or abnormal functioning of the PNS or CNS. It is manifested as ongoing nerve injury in either the PNS (e.g., postherpetic neuralgia, diabetic neuropathy) or the CNS (e.g., ischemic stroke, MS). Maladaptive pain may also be a result of disturbances in pain processing leading to hypersensitivity and spontaneous pain (e.g., FM, CD, tension headaches).

The treatment for pain should be individualized for each patient depending on the pathology and symptoms. The goals of pain management therapy are to improve the patient’s level of functioning, decrease pain perception, reduce the use of medications when possible, and improve the quality of life. Traditional medication therapies for pain include the use of NSAIDs (e.g., ibuprofen, naproxen), non-opioid analgesics (e.g., acetaminophen), tricyclic antidepressants (e.g., amitriptyline, imipramine), and anticonvulsants (e.g., gabapentin). These treatment options focus on reducing the inflammatory response to pain stimuli as well as inhibiting afferent pain stimuli by acting as ligands of alpha-2-delta voltage-gated calcium channels in the CNS. Low-dose and ultra-low-dose naltrexone (ULDN) have been investigated for the management of pain, complex regional pain syndrome (CRPS), and painful diabetic neuropathy with encouraging results.

Ultra-low-dose naltrexone has been investigated as an adjunct to opioid agonist therapy for pain. The concept of using a low-dose naltrexone in combination with an opioid agonist is not new. In fact, there have been opioid agonist-antagonist combination drugs approved by the FDA, including Embeda® (morphine/naltrexone as 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg,

80 mg/3.2 mg, 100 mg/4 mg) and Troxyca ER® (oxycodone/naltrexone as 10 mg/1.2 mg, 20 mg/2.4 mg, 30 mg/3.6 mg, 40 mg/4.8 mg, 60 mg/7.2 mg, 80 mg/9.6 mg).26-27

In a review article by Leri,28 opioid agonist and antagonist co-administration was investigated as a method to increase the desired effects of opioids and decrease the undesired effects. Leri stated that the effects of ULDN on, “analgesia, analgesic tolerance and opioid withdrawal have been consistently replicated.” Similarly, Hay, La Vincente, Somogyi, Chapleo, and White29 illustrated that ULDN significantly increased tolerance time to cold pressor pain compared to buprenorphine alone. These studies open the possibility of using ULDN as an adjunct to opioid pain management to increase the antinociceptive effects, ultimately reducing the dose needed for sufficient analgesia. This is likely due to the intermittent binding of ULDN to opioid receptors, resulting in the compensatory release of endogenous opioids. One of the more common side effects of opiate agonists is pruritus or itching. However, combination opiate agonist-antagonists have reduced the incidence of pruritus. Research into the effects of naltrexone cream and low-dose intravenous naltrexone has shown them to be significantly more effective at reducing pruritus associated with allergic dermatitis and liver disease, respectively.30

Firouzian et al.31 conducted a randomized, double-blind, placebo-controlled study to evaluate the effects of a single ultra-low-dose infusion of naltrexone on pain intensity after lumbar discectomy in patients receiving patient-controlled anesthesia (PCA) with morphine. Eighty patients were randomized to receive naloxone, at a total dose of 0.25 mcg/kg/hr added to the normal saline infusion, or placebo post-surgery. All patients received a morphine PCA pump. Patients graded pain intensity, nausea, vomiting, and pruritus on a 0-10 VAS prior to being discharged from the anesthesia unit, and at 1,6, 12, and 24 hours postoperatively. Infusion of ultra-low-dose naltrexone with morphine PCA resulted in a significant reduction in pain intensity, nausea, pruritus, and morphine consumption compared to the placebo group. The median (interquartile range) of morphine consumption after surgery was 26 (24.25 to 28) mg in the naloxone group compared to 34 (32—36) mg in the placebo group.

Xiao, Wu, Zhou et al.32 conducted a randomized clinical study also looking at the effects of ultra-low-dose naltrexone infusion on postoperative opioid requirements and recovery in 72 patients undergoing open colorectal surgery. Patients were randomized to receive intraoperative remifent- anil at either 0.1 mcg/kg/min, 0.30 mcg/kg/min, or 0.3 mcg/kg/min plus naltrexone at 0.25 meg/ kg/h after induction. Results showed that larger doses of remifentanil used intraoperatively triggered acute opioid tolerance postoperatively. Ultra-low-dose naltrexone improved opioid tolerance, improved functional recovery, and reduced the length of hospital stay.

A case report of a 35-year-old male with 2 years of chronic low back pain and a VAS score of 90-100 most of the time, interfering with daily activities, was initiated on 2 mg of LDN for 2 weeks, followed by an increase in dose to 4 mg daily at bedtime. At the time of presentation, his Modified Oswestry’s Disability Questionnaire (MODQ) was 65-70%. Lumbar magnetic resonance imaging revealed diffuse posterior bulge and right posterolateral disc perfusion at L5-S1, causing bilateral compression of neural foramina. This patient reported no appreciable response in pain at the 2 mg dose. Two weeks after the 4 mg dose was initiated, the patient reported a 30-40% reduction in pain. After 4 weeks on the 4 mg dose, his VAS score was 35 and MODQ was 35.5%. Low-dose naltrexone was stopped after 6 weeks of administration. At the last follow-up (6 months post-LDN initiation), the patient reported minimal pain and was able to participate in all daily activities. No adverse events were noticed during or after LDN treatment in the patient.33

In a case report of a 48-year-old male with a history of diabetes mellitus II, hypertension, hyperlipidemia, coronary artery disease, and widespread complex regional pain syndrome (CRPS), 4.5 mg of LDN daily reduced pain on the Numeric Rating Scale (NRS) from an 8 to 10 prior to treatment to an NRS pain level of 5 to 6 after starting treatment. This patient was also receiving low-dose ketamine infusions prior to and during LDN treatment. After LDN treatment, this patient required lower doses of IV ketamine at decreased frequency (6-week intervals versus 3-week intervals with pain spikes not as high). The patient also recovered from CRPS flares more quickly, felt more energetic, tolerated pain better, and slept better within 2 months of treatment. His dystonic spasms stopped, and he was able to walk without a cane. It was noted that this patient’s symptoms reduced in severity but not in distribution. Low-dose naltrexone was well-tolerated.34 Therapy with LDN is thought to help reduce pain by antagonizing TLR4, which are upregulated in microglia cells in the CNS, thereby reducing inflammatory markers in the CNS.35 36

In a second case exploring the use of LDN therapy in CRPS, a 12-year-old female with a history of Ehlers-Danlos syndrome (EDS) hypermobility type 1, dysautonomia, non-epileptic seizures, chronic gastritis, mitochondrial dysfunction, asthma, vision loss, thyroid tumor, and anti-cardio- lipin antibodies was prescribed LDN 3 mg daily, in addition to ketamine troches (sublingual) 10 mg as needed. After 4 weeks, LDN was increased to 4.5 mg daily. After starting LDN, her pain scores dropped from an NRS of (7—10)/10 to an NRS of (3—5)/10. She also noted a decrease in allodynia and a decrease in sensitivity to touch and temperature change. There was no effect on dystonia. The patient was able to progressively reduce the use of ketamine troches 3 weeks after starting LDN and was taking them rarely after 8 weeks. Treatment with LDN was temporarily discontinued due to an ankle surgery and reinstated after 1 week postoperatively. The patient noticed a decrease in her postoperative pain 3 weeks after resuming LDN, with no spread of CRPS. The symptoms of CRPS resolved completely and LDN was well-tolerated. At the time of this case report, the patient had been maintained on LDN for 18 months.34

In a case report of a 76-year-old male with a 30-year history of type 2 diabetes and 7-year history of diabetic neuropathy, LDN therapy was associated with an improvement in VAS, short form McGill pain questionnaire, and 11-point Likert pain scale scores. The patient had previously tried amitriptyline, pregabalin, duloxetine, lamotrigine, NSAIDs, injectable vitamin B-complex, and injectable vitamin D in varying doses and combinations for 1-2 months with little to no relief. Naltrexone was administered at 1 mg for 2 weeks, 2 mg for 2 weeks, and finally 4 mg for 2 weeks. The patient did not show a response to the 1 mg dose; however he showed partial improvement in burning pain with the 2 mg dose. At 4 mg, the patient showed a reduction in VAS scores from 90% to 5%, the short form McGill pain questionnaire from 8 to 1, and the 11-point Likert scale from 8 to 2.37

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