Methods of treatment of osteoarthritis with transdermal cannabidiol gel

Abstract

To provide a method for treating osteoarthritis.SOLUTION: A method is disclosed for treating one or more symptoms of osteoarthritis in a patient, wherein the method includes transdermally administering an effective amount of cannabidiol (CBD) to the patient, wherein one or more symptoms of osteoarthritis are treated in the patient.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 545,468, filed August 14, 2017, and U.S. Provisional Application No. 62 / 661,733, filed April 24, 2018, the entire disclosures of each of which are incorporated herein by reference.

[0002] The present disclosure relates generally to methods of treating osteoarthritis, and in particular to methods of treatment involving transdermal administration of cannabidiol gel. [Background technology]

[0003] The present disclosure relates to the treatment of osteoarthritis using cannabidiol. Cannabidiol (CBD) has the formula: [ka] It is a cannabinoid having the formula:

[0004] Osteoarthritis is a joint degenerative disease characterized by loss of cartilage and abnormal bone growth in the patient's joints. Symptoms include stiffness and pain, which can lead to reduced or impaired function. Osteoarthritis is estimated by the Centers for Disease Control and Prevention (CDC) to affect more than 30 million adults in the United States.

[0005] The treatment of osteoarthritis known in the art includes, in particular, opioid analgesics.In recent years, the abuse of opioid analgesics has become a major problem.Other existing treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors.These treatments may have an unfavorable side effect profile.

[0006] Many osteoarthritis patients who use currently available drugs either do not experience relief of pain and improvement in physical function, or cannot tolerate the medication due to side effects.

[0007] Assessment of pain, stiffness and physical function can be used to determine whether a patient's osteoarthritis symptoms are improving. The Western Ontario-McMaster Osteoarthritis Index (WOMAC) is a set of standardized questionnaires used by doctors and clinicians to assess the status of patients with osteoarthritis of the knee and hip. It includes assessment of joint pain, stiffness, and physical function. The WOMAC consists of 24 items divided into three subscales, measuring 5 items for pain, 2 items for stiffness, and 17 items for functional limitations. Summary of the Invention [Means for solving the problem]

[0008] Recent behavioral and electrophysiological studies have demonstrated that cannabinoids exert antinociceptive effects in rodent models of osteoarthritis. Cannabidiol (CBD) is known to have antihyperalgesic effects through its interaction with the TRPV1 receptor. CBD binds to adenosine receptors (A 2A ) and activate A 2A CBD has broad anti-inflammatory effects throughout the body. By blocking GPR55 signaling, which promotes osteoclast function, CBD can act to reduce bone resorption.

[0009] Cannabidiol (CBD) can provide treatment for osteoarthritis patients. The study disclosed herein shows that administration of CBD transdermal gel to the skin of osteoarthritis patients demonstrated improvement in combined pain / function metrics (composite responders). The study revealed particularly good results for male patients and those who reported high baseline pain scores at the start of the study. Furthermore, the study showed that treatment of patients with lower doses of cannabidiol, such as 250 mg per day, provided improved results than a dose of 500 mg per day. The present disclosure offers numerous advantages. Transdermal delivery of CBD may have benefits over oral dosing, as it allows the drug to be absorbed directly into the bloodstream through the skin. This avoids first-pass hepatic metabolism, potentially allowing for lower dosage levels of the active pharmaceutical ingredient with higher bioavailability and improved safety profile. Transdermal delivery also avoids the gastrointestinal tract, reducing the chance of GI-related adverse events and the possibility of CBD being decomposed by stomach acid into THC, which may be associated with undesirable psychoactive effects.The treatment provided herein can reduce the frequency and severity of pain experienced by patients.The treatment has limited side effects.The treatment can be used, for example, for those who do not respond well to existing treatments, those who experience negative side effects associated with such treatments, or when patients desire non-opioid treatments in the case of opioid treatments.

[0010] In one embodiment, a method of treating one or more symptoms of osteoarthritis in a patient is disclosed. The method includes transdermally administering an effective amount of cannabidiol (CBD) to the patient, whereby one or more symptoms of osteoarthritis are treated in the patient.

[0011] In some embodiments, the effective amount is 250-500 mg per day. The effective amount may be about 250 mg per day. The effective amount may be 500 mg per day. In some embodiments, the effective amount is 125 mg.

[0012] In some embodiments, the CBD is (-)-CBD. The CBD can be synthetic CBD. The CBD can be purified CBD. In some embodiments, the CBD is plant-derived CBD.

[0013] The CBD may be formulated as a gel. In some embodiments, the CBD is formulated as a penetration enhancing gel.

[0014] In some embodiments, the cannabidiol is in a pharmaceutical composition and the concentration of the cannabidiol in the pharmaceutical composition is between 3% and 5%. In some embodiments, the cannabidiol is in a pharmaceutical composition and the concentration of the cannabidiol in the pharmaceutical composition is 4.2%.

[0015] Administering an effective amount of cannabidiol transdermally may include applying to the patient's skin a gel suitable for transdermal application.

[0016] In some embodiments, the CBD is administered in a single dose per day. The CBD may be administered in two doses per day.

[0017] Transdermal administration of an effective amount of CBD may reduce the intensity of the mean worst knee pain score compared to baseline. In some embodiments, the one or more symptoms that are alleviated are knee pain. The one or more symptoms that are alleviated may be pain and function. In some embodiments, alleviating one or more symptoms of osteoarthritis may include an improvement in physical function WOMAC score. Alleviating one or more symptoms of osteoarthritis may include an improvement in composite response analysis. In some embodiments, alleviating one or more symptoms of osteoarthritis may include an improvement in pain and function. [Brief description of the drawings]

[0018] The present invention can be more fully understood from the following detailed description taken in conjunction with the accompanying drawings. [Figure 1] FIG. 1 shows a graph of the average weekly mean worst knee pain scores over time by treatment group. [Diagram 2] FIG. 2 shows a chart of the mean reduction from baseline to week 12 in mean worst knee pain score. [Diagram 3] FIG. 3 shows a graph of the mean percent change in mean worst knee pain score per week over time by treatment group. [Figure 4] FIG. 4 shows a chart of composite responders at last observation carried forward (LOCF), where composite responders are patients with ≧30% reduction in pain and 20% response in WOMAC physical function. [Diagram 5] FIG. 5 shows a graph of the median mean weekly worst knee pain scores over time by treatment group and gender (male). [Figure 6] FIG. 6 shows a chart of composite responders at LOCF for men only. [Figure 7] FIG. 7 shows a graph of the median mean weekly worst knee pain scores over time by treatment group and gender (female). [Figure 8] FIG. 8 shows a graph of the median mean worst weekly knee pain score over time and baseline score by treatment group for patients with a baseline pain score greater than or equal to 7. [Figure 9] FIG. 9 shows a chart of the mean reduction from baseline to week 12 in mean worst knee pain score for or patients with a baseline pain score greater than or equal to 7. [Figure 10] FIG. 10 shows a graph of the median mean worst weekly knee pain score over time and baseline score by treatment group for patients with a baseline pain score less than 7. [Figure 11] 11A and 11B show charts of the composite response in patients with (11A) and without (11B) selected medical history. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The present disclosure generally relates to administration of a CBD medicament to a patient's skin for transdermal penetration through and into the skin layers for delivery to the patient's bloodstream.

[0020] As used herein, the term "cannabidiol" or "CBD" refers to cannabidiol; cannabidiol prodrugs; pharma- ceutically acceptable derivatives of cannabidiol, such as cannabidiol, cannabidiol prodrugs, and pharma- ceutically acceptable salts of cannabidiol derivatives. CBD includes 2-[3-methyl-6-(l-methylethenyl)-2-cyclohexen-l-yl]-5-pentyl-l,3-benzenediol, as well as its pharma- ceutically acceptable salts, solvates, metabolites (e.g., skin metabolites), and metabolic precursors. The synthesis of CBD is described, for example, in Petilka et al., Helv.Chim.Acta, 52:1102 (1969) and Mechoulam et al., J.Am.Chem.Soc, 87:3273 (1965) (incorporated herein by reference).

[0021] As used herein, the term "treat" or "treatment" refers to alleviating, ameliorating, alleviating, or relieving at least one symptom of a condition, disease, or disorder in a subject, such as a human, or the improvement of an identifiable measure associated with a condition, disease, or disorder.

[0022] As used herein, the term "transdermally administering" refers to contacting the CBD with the skin of a patient or subject under conditions effective for the CBD to penetrate the skin.

[0023] As used herein, the term "clinical efficacy" refers to the ability to produce a desired effect in humans as demonstrated through clinical trials by the Food and Drug Administration (FDA), or any foreign counterpart.

[0024] As used herein, a medicament includes any ointment, cream, solution, suspension, lotion, paste, gel, hydrogel, spray, foam, solid or oil that can be made or formed and used to administer CBD or a CBD prodrug to a mammal, either alone or in combination with a bandage, patch or the like.

[0025] CBD can be delivered transdermally to a patient by topically applying a CBD medicine. In addition to inert diluents and carriers, CBD medicines can contain other excipients, such as wetting agents, preservatives, suspending agents and dispersing agents. In addition to these generally inactive ingredients, topical formulations containing CBD can further contain additional active agents, particularly active agents for treating pain, discomfort, or otherwise treating a patient's ailment. For example, active materials can include analgesics, such as opiates and other analgesic active agents that act on receptors other than the CBD receptor.

[0026] The topical formulation may be applied directly to the skin and then optionally covered (e.g., with a bandage or gauze) to minimize the possibility of movement. Alternatively, the topical formulation may be coated onto the surface of or absorbed into the bandage, gauze, etc., such that the topical medication directly contracts with the patient's skin. The gel does not need to be administered in close proximity to the patient's arthritic joint or joints.

[0027] An effective amount as described herein may be, for example, a daily dose of about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, or about 700 mg. Any of the above values ​​may form a range, for example, the daily dose may be about 125 mg to about 325 mg.

[0028] The effective amount as described herein can be a daily dose of about 250 mg per day or about 500 mg per day. The dose can be administered as a single dose per day, or the dose can be administered as two doses per day, for example, 125 mg twice a day or 250 mg twice a day.

[0029] The CBD may be in gel form and may be pharma- ceutical manufactured as a clear penetration enhancing gel designed to provide controlled drug delivery transdermally with one or two doses per day. The CBD gel may be 1% (wt / wt) CBD to 7.5% (wt / wt) CBD. The CBD gel may have, for example, 4.2% (wt / wt) CBD or 7.5% (wt / wt) CBD. The CBD gel may be applied topically by the patient or a caregiver to the patient's upper arms and shoulders, back, thighs, or any combination thereof.

[0030] Cannabidiol compositions may include one or more of each of penetration enhancers, solubilizers, solubilizers, antioxidants, bulking agents, thickeners, or pH adjusters. Examples of the above ingredients are described in the Handbook of Pharmaceutical Excipients (herein incorporated by reference). Penetration enhancers include isostearic acid, octanoic acid, oleic acid, oleyl alcohol, lauryl alcohol, ethyl oleate, isopropyl myristate, butyl stearate, methyl laurate, diisopropyl adipate, glyceryl monolaurate, tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol, diethylene glycol monomethyl ether, alkylaryl ether of polyethylene oxide, polyethylene oxide monomethyl ether, polyethylene oxide dimethyl ether, dimethyl sulfoxide, glycerol, ethyl acetate, acetoacetate, N-alkylpyrrolidone, and combinations thereof.

[0031] CBD gels may include solubilizing agents, penetration enhancers, solubilizers, antioxidants, bulking agents, thickeners, and / or pH adjusters. The composition of a CBD gel may be, for example, a. cannabidiol present in an amount of about 0.1% to about 20% (wt / wt) of the composition; b. a lower alcohol having 1-6 carbon atoms present in an amount of about 15% to about 95% (wt / wt) of the composition; c. a first permeation enhancer present in an amount of about 0.1% to about 20% (wt / wt) of the composition; and d. water in an amount sufficient to total up to 100% (wt / wt) of the composition. Other formulations of CBD gels can be found in International Publication No. WO 2010 / 127033, the entire contents of which are incorporated herein by reference.

[0032] The CBD medicine may be stored in a bottle, tube, packet, sachet, pouch, or similar packaging. Sachets, particularly disposable sachets, may be provided such that the amount of medicine in the sachet is suitable for a single use. EXAMPLES

[0033] Three hundred twenty patients aged 41-78 years with confirmed osteoarthritis of the knee were randomized in a double-blind, multicenter study. Patients who completed a 1-week washout and a 7-10 day baseline phase were randomized 1:1:1 to receive either 250 mg CBD per day, 500 mg CBD per day, or placebo for 12 weeks. Enrolled patients had a mean worst knee pain score of 6.9 on a scale of 1-10 during baseline. The 250 mg and 500 mg doses were administered as a 4.2% (wt / wt) CBD gel. Patient characteristics are shown in Table 1, and patient demographics for the safety analysis set are shown in Table 2.

[0034] [Table 1]

[0035] [Table 2]

[0036] Among all participants, patients on a 250 mg / day CBD dose achieved a mean reduction from baseline of 2.64 in mean worst knee pain score at week 12, patients on a 500 mg / day CBD dose achieved a mean reduction from baseline of 2.83 in mean worst knee pain score at week 12, and placebo patients achieved a mean reduction from baseline of 2.37 in mean worst knee pain score at week 12. These results were not statistically significant. Figures 1 and 2 show the average weekly mean worst knee pain scores over time by treatment group, indicating that pain decreased in both the active group and the placebo. Figure 3 shows the mean percent change in mean weekly mean worst knee pain score corresponding to the results shown in Figure 1. A mixed model repeated measures (MMRM) model was used to test for differences between the active treatment group and placebo based on all weekly mean worst knee pain scores from baseline to week 12.

[0037] During the first 7-day period, patients were instructed to discontinue use of other osteoarthritis treatments, such as NSAIDs or COX-2 inhibitors, but were allowed to use acetaminophen for rescue use. At this time point, baseline mean worst knee pain was identified for each patient. Rescue use of acetaminophen was allowed for both the active and placebo test groups during the study, with no difference between groups in frequency of rescue use.

[0038] As shown in FIG. 4, a statistically significant result was achieved for the composite responder (i.e., number and percent of patients with a mean weekly improvement in worst pain score of ≥30% at last observation carried forward and a reduction in the WOMAC physical function subscale of ≥20% at last observation carried forward (LOCF)) analysis for 250 mg CBD per day (p=0.016). Fisher's exact test was used to test for composite responder differences between each active treatment and placebo at LOCF. In the composite responder analysis, a positive response in the composite response analysis indicated a reduction in worst mean daily pain score of ≥30 percent and an improvement in the WOMAC (Western Ontario-McMaster Universities Osteoarthritis Index) physical function score of ≥20 percent. Thus, a positive composite response score demonstrates improvement in both pain and function. The composite responder score is considered to be more effective in distinguishing the effect of the drug from placebo because it includes both pain and function components.

[0039] A summary of the composite responder analysis at the last observation is reported in Table 3. Table 3 shows that 60 of 93 patients experienced a 20% or greater response in physical function WOMAC score after treatment with 250 mg of CBD in a 4.2% CBD gel per day. Furthermore, in 53 of 106 patients, a reduction in pain of at least 30% was observed, and 49 of 93 (52.7%) exhibited a composite response.

[0040] [Table 3]

[0041] Statistically significant results were also recorded for responder rate based on a ≥ 30% reduction in worst pain severity (p = 0.037) for 250 mg CBD per day at week 8. Trends toward statistical significance were observed for other secondary endpoints.

[0042] In addition to demonstrating the value of cannabidiol for osteoarthritis, the data also provide information regarding dosage levels. A dose of 250 mg of cannabidiol per day shows better results than 500 mg per day in the composite assessment and each component of the composite assessment. See Figure 6. Furthermore, the trend for improvement from 500 mg to 250 mg suggests that doses lower than 250 mg may provide similar or greater benefit to patients. The dose / weight analysis discussed below specifically supports a reduced dose (less than 250 mg) to achieve the good results observed for treatment at the lower dose / weight.

[0043] Safety Data: CBD gel was shown to be very well tolerated, and the safety profile was consistent with data from previously reported clinical trials. Table 4 provides a summary of adverse events.

[0044] [Table 4]

[0045] Pharmacokinetic Data: Administration vehicle plasma concentrations for the 500 mg and 250 mg daily CBD doses were dose proportional, with the 500 mg dose level approximately twice the plasma concentration of the 250 mg dose.

[0046] The data obtained in the study described in Example 1 was also analyzed by gender. Men on 250 mg CBD per day achieved a mean reduction from baseline of 1.65 in mean worst knee pain scores at week 4, compared to a mean reduction from baseline of 1.19 in placebo men (p=0.156); a mean reduction from baseline of 2.30 in mean worst knee pain scores at week 8, compared to a mean reduction from baseline of 1.56 in placebo men (p=0.066); and a mean reduction from baseline of 2.68 in mean worst knee pain scores at week 12, compared to a mean reduction from baseline of 1.70 in placebo men (p=0.049).

[0047] [Table 5]

[0048] Figure 5 shows the median mean weekly worst knee pain scores over time for men, who experienced a significant reduction in mean knee pain scores for both 250 mg CBD and 500 mg CBD versus placebo, with the lowest mean pain scores reported for patients given 250 mg CBD at study endpoint. Figure 6 shows composite responders in LOCF for men only.

[0049] As shown in Figure 6, female patients showed a reduction in pain, but the female placebo group demonstrated a greater reduction in pain. Women did not achieve significance at the endpoint. Figure 7 shows the median mean weekly worst knee pain scores over time for female patients, showing that pain decreased for both the active and placebo arms over the course of the study, but was not significant at the end of the study.

[0050] The data obtained in the study was also analyzed with respect to response at different levels of pain severity, showing greater efficacy in patients with higher baseline pain scores. The mean baseline worst knee pain score was 6.9. In the evaluation of patients with a baseline pain score of ≧7, there were 101 patients in the CBD arm and 48 patients in the placebo arm within this baseline. CBD patients achieved a mean reduction from baseline of 2.17 in mean worst knee pain score at week 4, compared to a mean reduction from baseline of 1.6 in placebo patients (p=0.029); a mean reduction from baseline of 3.02 in mean worst knee pain score at week 8, compared to a mean reduction from baseline of 2.22 in placebo patients (p=0.054); a mean reduction from baseline of 3.29 in mean worst knee pain score at week 12, compared to a mean reduction from baseline of 2.52 in placebo patients (p=0.086). See Figure 9.

[0051] [Table 6]

[0052] FIG. 8 shows that knee pain scores for patients with a baseline knee pain score greater than or equal to 7 were reduced to a greater extent than placebo for both 250 mg CBD and 500 mg CBD. FIG. 9 shows the mean reduction from baseline to week 12 in mean worst knee pain score for patients with a baseline knee pain score greater than or equal to 7. The data in FIG. 9 are presented as placebo group vs. combination CBD transdermal gel (i.e., both dose groups combined). By comparison, FIG. 10 shows the corresponding data for patients with a baseline knee pain score less than 7. For this group, the reduction in pain relative to placebo was not statistically significant.

[0053] The above results in Tables 5 and 6 can also be compared to all patent totals, which are reported in Table 7, demonstrating that the results for male patients and patients with baseline pain greater than or equal to 7 show a greater reduction in pain for the overall study population, with a relatively smaller reduction associated with placebo.

[0054] [Table 7]

[0055] Variability in baseline pain scores affects efficacy. Table 8 shows the composite response as a function of baseline pain standard deviation.

[0056] [Table 8]

[0057] Composite response was also analyzed in patients with and without a selected medical history. Selected medical history consisted of central neuropathic pain, fibromyalgia, depression, mood changes, dysphoria, fatigue and / or insomnia. Figure 11A and Figure 11B are charts detailing the composite response in patients with and without a selected medical history.

[0058] The study data were also analyzed with respect to active agent dose per patient weight (i.e., mass of CBD in mg administered / kg patient weight). For this analysis, the patient population was divided into three groups by dose / weight: 0-25th percentile, 25-75th percentile, and 75-100th percentile. Table 9 summarizes the composite responder analysis in the 0-25% dose / weight quartile at last observation. Table 10 summarizes the composite responder analysis in the 25-75% dose / weight quartile at last observation. Table 11 summarizes the composite responder analysis in the 75-100% dose / weight quartile at last observation.

[0059] [Table 9]

[0060] [Table 10]

[0061] [Table 11]

[0062] This analysis showed that patients in the 0-25th percentile group exhibited the greatest percentage of combined responders, with 27 of 46 (58.7%) exhibiting both a 30 percent reduction in pain and a 20 percent response in physical function WOMAC score. Overall, 69.6% of patients in this group demonstrated a 20 percent response in physical function WOMAC score. In contrast, less than half of the patients in the 25-75th percentile group exhibited a combined response (46.8% for the 250 mg CBD and 48.9% for the 500 mg CBD subset). For the 75-100th percentile group, only 41.3% exhibited a combined response. Thus, the dose / weight analysis showed that lower doses / weight were more effective. Furthermore, the analysis allows for the comparison of two groups of 250 mg CBD patients, namely those receiving a lower dose / weight (0-25th percentile) and a higher dose / weight (25-75th percentile). This comparison shows that within the 250 mg CBD group, the lower dose / weight demonstrated better composite responder scores. This trend indicates that a dose lower than 250 mg may be beneficial for patients. A dose lower than 250 mg allows more patients to fall into the lower dose / weight range of the active agent demonstrated herein to produce favorable results.

[0063] Summary of Results Neither the 250 mg nor the 500 mg dose of the CBD transdermal gel group demonstrated a statistically significant separation from placebo in terms of mean reduction from baseline to week 12 in mean worst knee pain score. The analysis revealed that a significant separation of CBD transdermal gel versus placebo was observed for those with a baseline PAGE score ≥ 7. The analysis highlighted that women exhibited a greater placebo response than men.

[0064] A significantly greater number of patients receiving 250 mg of CBD transdermal gel per day (52.7%) were combined responders compared to those receiving placebo (34.1%). Analysis revealed that the differences from placebo for both the 250 mg and 500 mg groups were greater among those who had a change in lease amount in baseline pain scores.

[0065] All publications and references referred to herein are expressly incorporated herein by reference in their entirety.

Claims

1. 1. A method of treating one or more symptoms of osteoarthritis in a patient, comprising:

1. A method comprising transdermally administering to said patient an effective amount of cannabidiol (CBD), wherein one or more symptoms of osteoarthritis are treated in said patient.

2. 2. The method of claim 1, wherein the effective amount is 250 to 500 mg per day.

3. 2. The method of claim 1, wherein the effective amount is about 250 mg per day.

4. 2. The method of claim 1, wherein the effective amount is 500 mg per day.

5. 2. The method of claim 1, wherein the CBD is (-)-CBD.

6. 10. The method of claim 1, wherein the CBD is formulated as a gel.

7. 7. The method of claim 6, wherein the CBD is formulated as a penetration enhancing gel.

8. 2. The method of claim 1, wherein the effective amount is about 125 mg.

9. 10. The method of claim 1, wherein the cannabidiol is in a pharmaceutical composition and the concentration of cannabidiol in the pharmaceutical composition is between 3% and 5%.

10. 2. The method of claim 1, wherein the cannabidiol is in a pharmaceutical composition and the concentration of cannabidiol in the pharmaceutical composition is 4.2%.

11. 10. The method of claim 1, wherein administering an effective amount of cannabidiol transdermally comprises applying to the patient's skin a gel suitable for transdermal application.

12. 10. The method of claim 1, wherein the CBD is administered in a single dose per day.

13. 10. The method of claim 1, wherein the CBD is administered in two doses per day.

14. 2. The method of claim 1, wherein the CBD is synthetic CBD.

15. 2. The method of claim 1, wherein the CBD is purified CBD.

16. 2. The method of claim 1, wherein the CBD is derived from a plant.

17. 2. The method of claim 1, wherein administering an effective amount of CBD transdermally reduces the intensity of the mean worst knee pain score compared to baseline.

18. 10. The method of claim 1, wherein the one or more symptoms relieved is in knee pain.

19. 10. The method of claim 1, wherein the one or more symptoms relieved are pain and function.

20. 10. The method of claim 1, wherein reducing one or more symptoms of osteoarthritis comprises an improvement in physical function WOMAC score.

21. 10. The method of claim 1, wherein reducing one or more symptoms of osteoarthritis comprises an improvement in a composite response analysis.

22. 10. The method of claim 1, wherein reducing one or more symptoms of osteoarthritis comprises improved pain and function.

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