December 6, 2023

A Multimodal Approach to Pain From Disc Herniation

Results from a 4-arm study
Incorporating the multi-modal approach to treatment design with a study of acute low-back pain as a guide.


Latini E, Bonasia G, Petroselli L, et al. Alpha-lipoic acid, palmitoylethanolamide, myrrh, and oxygen-ozone therapy improve pharmacological therapy in acute painful lumbosacral radiculopathy due to herniated disc. Pain Physician. 2023;26(4):E363-E373. 

Study Objective

The researchers investigated whether the effects of a combination of nutraceutical supplements and oxygen-ozone (O2-O3) therapy, in addition to pharmacological therapy, would improve clinical outcomes for pain and reduce disability in patients with acute radicular low-back pain (LBP).

Key Takeaway

Acute low-back pain is a major concern. The use of a combination of treatments, including neurotrophic, antioxidant, and analgesic therapies, shows statistically significant changes in functional disability indices of physical and mental health parameters. Addressing the problem from an etiopathogenetic approach not only reduces symptomatology, but can also avoid the progression of nerve damage that can occur during the current model of isolated, symptomatic treatment. 


Prospective, open-label, comparative, observational study with 4 arms 


This trial involved a total of 62 patients. The trial was open to those aged 18 to 75 years, with a lumbosacral magnetic resonance imaging (MRI) or computed tomography (CT) scan confirming diagnosis of disc herniation and clinical presentation of acute radicular low-back pain.

Investigators defined “acute” as less than 3 months, and they assessed severity via the Numeric Rating Scale (NRS-11), including only those with moderate or severe pain (NRS-11 ≥6).

Recruitment took place from April 2021 to March 2022 at the Physical Medicine and Rehabilitation Unit of Sant’Andrea Hospital in Rome, Italy, and was open to both men and women with acute lumbosacral radiculopathy.

Exclusion criteria included pain lasting more than 3 months; severe neurological deficit; cauda equina syndrome; other spinal disorders such as lumbar spinal stenosis, lumbar spondylolisthesis, ankylosing spondylitis, or spinal tuberculosis; previous lumbar surgery; contraindications for corticosteroids; any contraindication to paravertebral infiltrative therapy with O2-O3; glucose-6-phosphate dehydrogenase deficiency (favism); uncontrolled hyperthyroidism; severe cardiovascular diseases and heart failure; any condition for which surgical treatment of the spine is recommended; and diabetes mellitus.


Investigators obtained baseline data from the eligible participants after their written consent. They assigned participants to study groups according to medical history and clinical and instrumental evaluations. 

There were 3 time points: T0, or baseline; T1=2 weeks of treatment; and T3=4 weeks of treatment.

Investigators then assigned 62 patients with acute lumbosacral radiculopathy to 4 treatment groups (A–D):

  • Group A: 16 patients received solely the pharmacological therapy;
  • Group B: 15 patients received both the pharmacological therapy and the nutraceutical compound;
  • Group C: 15 patients received the pharmacological treatment along with the paravertebral O2-O3 therapy intramuscularly; and
  • Group D: 16 patients received all 3—the pharmacological therapy, the nutraceutical compound, and the O2-O3 therapy intramuscularly. 

The drug details: The pharmacological therapy consisted of betamethasone disodium phosphate. Participants received 4 mg/2mL intramuscularly twice daily during week 1 and once daily in week 2; they then received an oral dose of 2 tablets betamethasone disodium phosphate, 1 mg, once daily in week 3. 

The supplement details: The study used a nutraceutical compound called Tiobec® Dol from the company Uriach Italy Srl). It is composed of alpha-lipoic acid (ALA, 404 mg), nonmicronized palmitoylethanolamide (non-m-PEA, 306 mg), and myrrh (Commiphora myrrha [Nees] Engl, oleum-gummi-resina, 100 mg). 

The ozone details: The paravertebral intramuscular O2-O3 therapy, known for its immunomodulatory, analgesic, anti-inflammatory, and antioxidant properties, consisted of a total of 8 intramuscular injections, administered 2 times weekly in the paravertebral muscles of the corresponding affected vertebral segments for the duration of the 4-week intervention period. Under sterile conditions, 2 symmetrical injections of 10 mL of the O2-O3 gaseous mixture (15 μg/mL concentration) were injected at 2 cm laterally from the spinous processes of the paravertebral muscles.

The same physiatrist assessed each group for the duration of the study and met with that doctor at T0 to initiate the respective treatment intervention; at T1, 2 weeks later; and then at T2, 4 weeks after T0 or treatment initiation. 

Study Parameters Assessed

Parameters measured in this study included subjective data as assessed via the Oswestry Disability Index (ODI), consisting of 10 items on pain and daily function, each item rated on a 6-point scale (0%=no disability and 100%=maximum disability).

Secondary outcomes used the following assessments:

  • the NRS-11 measurement scale to measure the pain levels; 
  • the Short-Form Health Survey (SF-12), divided into a 12-item Physical Component Summary (PCS-12); and 
  • the 12-item Mental Component Summary (MCS-12) to assess quality of life. 

Patients completed daily diaries from T0 (baseline) to T2 (end of treatment, 4 weeks later) to document any additional opioid analgesic intake.

Primary Outcome

The primary outcome this study assessed was the improvement in functional disability resulting from acute low-back pain in those with moderate or severe pain, a diagnosis of lumbar disc herniation, and radiculopathy. 

Secondary outcomes measured improvements in pain, quality of life (physical and mental), and number of days receiving opioid analgesic therapy. 

Key Findings

The study had a number of statistically significant key findings (P<0.05) among all 4 groups across the time parameters T1 and T2. The multimodal treatment groups improved significantly more, particularly in functional disability.

Mean differences in the NRS-11 scores were: for T0–T1, <0.001 for all groups; for T1–T2, 0.042 in Group A, 0.020 in Group B, <0.001 in Group C, and 0.002 in Group D; and for T0–T2, it was <0.001 among all groups. 

Changes in the ODI were as follows: for T0–T1, <0.001 in all 3 groups; for T1–T2, 0.026 in Group A, 0.011 in Group B, 0.002 in Group C, and 0.001 in Group D; and for T0–T2, 0.001 in Group A and <0.001 in Groups B–D.

Changes in the PCS-12 were as follows: for T0–T1, again <0.001 in all groups; for T1–T2, 0.031 in Group A, 0.008 in Group B, 0.002 in Group C, and 0.075 in Group D; and for T0–T2, <0.001 in all groups. 

MCS-12 results saw few statistically significant changes. These were noted for T0–T1 in Groups B, C, and D (0.002, 0.009, and <0.001, respectively). Midpoint did not have significant changes. For T0–T2, statistically significant changes occurred for all 4 groups. Specifically, Group A was 0.020; Group B 0.001; Group C 0.002; and Group D was 0.004. 

In group comparisons, the most significant changes occurred when all groups were compared with the pharmacological-therapy group but not when compared to each other with regard to perceived physical pain. Therefore, the other therapies were effective, not one more than the other, by the end of the study. At T1, perceived pain was more significant in Group B vs Groups C and D but not by the end of treatment. Thus, we could postulate that the O2-O3 therapy might take longer to work or the perceived pain may diminish when mental health scores improve. At the T1 evaluation, Group D did show differences in MCS-12 scores compared to Group A.

Comparisons in adjuvant opioid therapy were highest in Group A (mean=9 days), followed by Group B (6 days), and they were lowest in Groups C (3 days) and D (4 days). 

Although there were no statistically significant changes in the average days of opioid usage in the 4 treatment groups (8.33 in Groups A, B, and C and 8.75 in Group D), the percentage of participants utilizing adjuvant opioid therapy varied remarkably between groups: 60% in Group A, 40% in Group B, 20% in Group C, and 25% in Group D). 


The study occurred at the Physical Medicine and Rehabilitation Unit of Medical and Surgical Sciences and Translational Medicine, Sant’Andrea University Hospital in Sapienza University of Rome in Italy. The authors did not use any external funding to prepare the manuscript for publication, and each author certified that neither the researcher nor any family member had commercial associations that may impose a conflict of interest with the submission of the study manuscript.

Practice Implications & Limitations

This study used a multimodal and etiopathological approach to treat acute low-back pain. The inquiry assessed both pain reduction and initiation of targeted repair. 

Acute low-back pain is characterized by inflammation, oxidative stress, and nociception with possible dermatomal sensory and motor loss1; disc herniation is a condition in which a disc between the vertebrae is displaced.2

The International Association for the Study of Pain reported (via The Institute for Health Metrics and Evaluation’s 2019 statistics) that between 1990 and 2019, low-back pain increased in all age groups, with the greatest impacts seen in those aged 50 to 54 years. Moreover, there was a loss through disability in working-aged people (aged 20–65 years).3,4 However, many people work well beyond age 65, and other factors become greater risks for those beyond the age of 65, including bone density, decreased mobility, isolation, number of hours sitting, increased risk of falls, and all precipitating factors related to circulation that contribute to balance. For these reasons, treating low-back pain well is critical. When the pain is acute, this type of approach can begin to address root causes while also treating the immediate acute situation.

Acute situations are entry points for people to recognize the need for the type of care that naturopathic medicine provides.  

Whenever we evaluate a patient, we ask about contributing factors to the chief complaint. In this case, occupation can play a role, particularly when considering the possibility of recurrence. A study conducted in Sweden between 2015 and 2021 surveyed those exposed to various forms of cold in their respective workplaces. They reported that occupational ambient cold exposure worsens both low-back and neck/shoulder pain, with a higher percentage of females reporting neck and shoulder pain and radiating low-back pain and both genders reporting isolated low-back pain. There is a higher prevalence of all factors when cold exposure increases.5

Similar patterns have been illustrated in studies from multiple countries. A study from Finland found that the anatomical region most exposed to the cold will correlate to a higher risk of associated pain, with related factors such as the experience of drafts and cool air and prolonged exposure being associated with poor work ability and musculoskeletal problems.6

Hence, tailoring dosing and therapies to revolve around the aggravating factors and the times of increased and decreased stresses can potentially affect therapeutic efficacy and maintenance of lasting effect. 

The treatments for acute low-back pain are numerous. In the study reviewed here, Latini and colleagues used an approach that targeted different pathways for inflammation and evaluated progress as a decrease in pain and an increase in mobility; they used other indices to record changes in both physical and mental-health quality of life. 

The nutraceutical combination itself approached pain in a similar manner within the one supplement, paying heed to the pathways and aspects of injury. Alpha-lipoic acid is anti-inflammatory and oxidant scavenging7; PEA and myrrh address the resolution of inflammation; and PEA, known for its cannabinoid effects, has a neuroprotective effect.8

Both the oxygen-oxidation and nutraceutical supplement were used in combination with and compared to dexamethasone alone. Dexamethasone is a corticosteroid. The main effects of this class of drugs are to act as an anti-inflammatory and anti-edema agent. It is often prescribed only for a limited short time in most cases. However, the side effects and drug interactions listed are plentiful, and not all patients are candidates for this form of therapy.9

In Ukraine, a parallel-group, double-blind, randomized clinical trial evaluated the effects of intravenous (IV) dexamethasone vs L-lysine aescinate in 90 adult patients with acute lumbar radiculopathy with herniated lumbar disc. The researchers found significant improvements in sciatic pain with both therapies by the 30th day post-treatment. 

All patients were concomitantly administered the nonsteroidal anti-inflammatory drug (NSAID) lornoxicam (16 mg/day) along with the test therapy. The groups were administered the respective IV solutions daily for 5 days. The steroid group received a solution of dexamethasone IV, 8 mg per day; the L-lysine groups received 1 mg per 1 mL (0.1 solution) L-lysine, with one group receiving 5 mL and the last group 10mL in an IV infusion diluted in isotonic sodium chloride solution to 50 mL of total. Patients received baseline magnetic resonance imaging (MRIs) and were evaluated for pain using the Straight Leg Test and the Visual Analog Scale for global pain, measured for significance by the Brief Pain Inventory. 

They reported that occupational ambient cold exposure worsens both low-back and neck/shoulder pain.

Although levels of improvement were greater in the dexamethasone group by the 30th day post-treatment, the study also noted that, though not significant, hernia size had not increased, and no caudal migration occurred in the 10-mL L-lysine group; in the dexamethasone group, however, there were 3 cases of morphological deterioration.10

Oxygen-ozone therapy was the third modality chosen by Latini et al. It is another possible alternative to dexamethasone due to its multifactorial actions; it is both anti-inflammatory and antioxidant. 

A 2021 comprehensive review of oxygen-ozone therapy in the rehabilitation field stated that O2-O3 therapy may exert its mechanical effect via oxidation; this, in turn, may break down the glycosaminoglycan chains in the nucleus pulpolus, which then reduces the ability to retain water, decreases the hernia position, stimulates fibroblastic activity, and leads to collagen deposition and tissue-level repair. It may also exert anti-inflammatory processes by altering the breakdown of arachidonic acid to inflammatory prostaglandins.11

Other therapies to consider when thinking about pain—particularly acute, with the desire for quick relief from pain—can and should include homeopathy and potentially other hands-on therapies such as Bowen therapy and craniosacral therapy, as well as non-hands-on modalities like red light therapy, infrared sauna, and cryotherapy, for which there is a growing body of research. The latter therapy is effective for depression and also for reducing inflammatory markers in low-back pain. 

Low-back pain can significantly affect mental health. As clinicians, it is fundamental that this be addressed either verbally or through our senses of listening to the patient’s narrative and observing how they carry and move themselves through a place of distortion to their normal; through touch via physical exams; and from the sense we feel in the presence of the patient. Then, we should confirm our observations through unfazed inquiry. Tailoring treatment plans by learning who these patients are not only fosters our connection with others, but it also maintains our boundaries with them and, finally, guides our treatment and destination plans in partnership with those whom we serve. 

Depressed patients who end up with acute low-back pain may be less prone to holding therapeutic effect when and if the depression “gets in the way.” Cryotherapy may offer an alternate approach. One study evaluated mental-health state and quality of life using 10 cryotherapy sessions and found that more severely depressed patients benefited from cryotherapy more;12 a quasi-experimental study in Monterrey, Mexico, led by Salas et al, evaluated the inflammatory markers interleukin 2 (IL-2) and IL-10 in 41 patients with low-back pain and found significant decreases with the use of cryotherapy.13

Once again, the options are numerous, and knowing who may respond most to what and when is where our art can both shine and be fun when it does. 

There are multiple paths to follow in the world of treatment. A possible study or clinical trial may produce interesting outcomes—for example, the nutraceutical, the IV L-Lysine treatment, and the oxygen-ozone therapy in isolation and in combination. This would help to clarify the benefits of each in clinical outcome, revealing which patient profiles are most responsive to each respective therapy. Producing the greatest effect with the most effective minimum dose and cost to each patient is at the heart of our therapeutic principles.  

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