USE OF CO-CRYSTALS OF TRAMADOL AND CELECOXIB FOR TREATING PAIN WHILE REDUCING THE ABUSE LIABILITY OF TRAMADOL

Abstract

The present invention relates to the use of co-crystals of tramadol and celecoxib for the treatment of pain, preventing the risk of an addiction to tramadol, for the treatment of pain while reducing the abuse liability of tramadol, for the treatment of pain also reducing an incidence of addiction to tramadol, for the treatment of pain preventing an addiction to tramadol, for the treatment of pain in a patient with an addiction to tramadol or the risk of it, for the treatment of pain and inhibiting, delaying, reducing or reversing an addiction to tramadol or for treatment of pain and reducing an incidence of addiction to tramadol.

Claims

1-13. (canceled)

14. A method for the treatment of pain, while reducing the abuse liability of tramadol, in a patient in need thereof, comprising administration of an effective amount of a co-crystal of (rac)-tramadol.HCl and celecoxib, or a pharmaceutically acceptable derivative thereof, wherein the co-crystal is administered alone or in combination with one or more pharmaceutically acceptable excipients.

15. The method according to claim 14, wherein the molecular ratio between the (rac)-tramadol.HCl and celecoxib is 1:1.

16. The method according to claim 15, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with at least one of the peaks [2θ] selected from 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (Cu.sub.Kα1 1.54060 Å).

17. The method according to claim 15, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0 and 22.7[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å).

18. The method according to claim 17, characterized in that the co-crystal shows additional peaks [2θ] at 7.1, 19.9 and 20.5[°].

19. The method according to claim 18, characterized in that the co-crystal shows additional peaks [2θ] at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4 and 26.1 [°].

20. The method according to claim 15, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (Cu.sub.Kα1 1.54060 Å).

21. The method according to claim 15, characterized in that the co-crystal shows a Fourier Transform Infra Red pattern with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m) 625.9 (m) cm.sup.−1.

22. The method according to claim 15, characterized in that the co-crystal has an orthorhombic unit cell with the following dimensions: a=11.0323(7) Å b=18.1095(12) Å c=17.3206(12) Å.

23. The method according to claim 15, characterized in that for the co-crystal the endothermic sharp peak corresponding to the melting point has an onset at 164° C.

24. The method according to claim 14, wherein the pain is acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe to moderate pain, hyperalgesia, pain related to central sensitization, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy and osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica.

25. The method according to claim 24, wherein the pain is acute and chronic moderate to severe pain, acute moderate to severe pain, acute moderate pain, acute severe pain, chronic moderate to severe pain, chronic moderate pain, or chronic severe pain.

26. The method according to claim 14, wherein the co-crystal is administered as a pharmaceutical composition which further comprises at least a solubility enhancer polymer; wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or from copovidone, povidone, cyclodextrin, polyethylene glycol and lauroyl macrogol-32 glycerides EP.

27. The method according to claim 26, wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or other hydrophilic polymers selected from copovidone, or povidone.

28. The method according to claim 27, wherein the solubility enhancer polymer is copovidone.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0093] FIG. 1:

[0094] Linear profile of the mean plasma concentrations for tramadol and O-desmethyltramadol after oral administration to healthy male and female subjects of Co-crystal E-58425 (Treatment-1), Ultram® (Treatment-2) and Ultram®+Celebrex® (Treatment-4).

[0095] FIG. 2:

[0096] Abuse Quotient (AQ) for tramadol and its metabolite M1, obtained from Co-crystal E-58425 (Treatment-1) Ultram® (Treatment-2) and Ultram®+Celebrex® (Treatment-4) calculated from the data obtained in a 4-way cross-over study. For opioids, there is high correlation of the C.sub.max/T.sub.max ratio with pharmacodynamic effects, with higher C.sub.max/T.sub.max (faster and/or higher absorption) denoting greater abuse potential.

[0097] For Co-crystal E-58425, the AQs obtained for tramadol in the 4-way cross-over study were lower than those obtained for Ultram® and for Ultram® and Celebrex® taken concomitantly and these differences were statistically significant, suggesting a lower abuse potential for Co-crystal. No statistically significant differences were observed for Ultram® taken alone or in combination with Celebrex®.

Pharmacokinetic Parameter Definitions

[0098] C.sub.max Maximum observed plasma concentration [0099] T.sub.max Time of maximum observed plasma concentration [0100] AQ Abuse quotient [0101] HPLC High performance liquid chromatography [0102] MS/MS Triple quadrupole mass spectrometry [0103] IS1/ISTD1 Internal standard (tramadol-D6) [0104] IS2/ISTD2 Internal standard (O-desmethyltramadol-D6) [0105] K.sub.2-EDTA Di-potassium ethylene diamine tetraacetic acid [0106] LOQ Lower Limit of Quantitation [0107] M1: O-desmethyltramadol [0108] S.D. Standard Deviation [0109] SE Standard Error [0110] CV Coefficient variation [0111] mg Milligrams [0112] mL Milliliters [0113] ng Nanograms

Examples

[0114] The study was a single center, randomized, single dose, open-label, 4-period, 4-sequence, crossover design in healthy male and female subjects. The following treatments were administered under fasting conditions: [0115] Treatment-1: 2×100 mg Co-crystal E-58425 tablets, administered alone [0116] Treatment-2: 2×50 mg Tramadol HCl tablets (Ultram®), administered alone [0117] Treatment-3: 1×100 mg Celecoxib capsule (Celebrex®), administered alone (data not shown) [0118] Treatment-4: 2×50 mg Tramadol tablets (Ultram®) and 1×100 mg Celecoxib capsule (Celebrex®), taken concomitantly.

[0119] The products were administered to 36 subjects. The wash-out between the periods for each subject was of 7 calendar days.

TABLE-US-00002 TABLE 1 Study Sequences Period 1 Period 2 Period 3 Period 4 Sequence 1 (n = 9) Treatment-1 Treatment-2 Treatment-4 Treatment-3 Sequence 2 (n = 9) Treatment-2 Treatment-3 Treatment-1 Treatment-4 Sequence 3 (n = 9) Treatment-3 Treatment-4 Treatment-2 Treatment-1 Sequence 4 (n = 9) Treatment-4 Treatment-1 Treatment-3 Treatment-2

[0120] Handling of Samples

[0121] Separate blood samples were obtained for analysis of tramadol/M1 metabolite and for analysis of celecoxib (data not shown). Blood samples for quantification of tramadol and M1 metabolite (Treatment-1, Treatment-2 and Treatment-4) were collected prior to drug administration and at 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36 and 48 hours after drug administration in K.sub.2-EDTA Vacutainers.

[0122] As soon as possible following blood collection, samples were centrifuged at a temperature of 4° C. nominal and at approximately 1500 g for 10 minutes. The plasma obtained was separated into duplicate polypropylene culture tubes. Each tube was labeled in order to identify the drug to be assayed and with a code number that did not reveal formulation identity. The samples were frozen in an upright position and retained in the clinic's freezers at a temperature of −20° C. nominal until sent on dry ice to the bioanalytical facility for assay.

[0123] Method of Measurement

[0124] The experimental human plasma samples were assayed for tramadol and M1 metabolite (0-desmethyltramadol) and also for celecoxib (data not shown) using two different validated bioanalytical methods by HPLC with MS/MS detection.

[0125] Sample pre-treatment involved the liquid-liquid extraction of tramadol and O-desmethyltramadol from 0.100 mL of human plasma; tramadol-D6 and O-desmethyltramadol-D6 were used as the internal standards (IS1 and IS2 respectively). The compounds were identified and quantified using Hilic HPLC with MS/MS detection over a theoretical concentration range of 2.00 ng/mL to 800.00 ng/mL for tramadol and 0.500 ng/mL to 200.00 ng/mL for O-desmethyltramadol. The concentrations were calculated using peak area ratios and the linearity of the calibration curve was determined using a weighted (1/x.sup.2) linear (y=mx+b) least squares regression analysis for tramadol and for O-desmethyltramadol.

[0126] Pharmacokinetic Analysis

[0127] Pharmacokinetic parameters were estimated from the individual plasma concentration—time profile for each subject. The main absorption and disposition parameters were obtained using a non-compartmental approach with a log-linear terminal phase assumption. Maximum observed plasma concentration (C.sub.max) and the time of maximum observed plasma concentration (T.sub.max) were obtained directly from the experimental data. The trapezoidal rule was used to estimate the area under the curve (AUC; data not shown) and the terminal phase was estimated by maximizing the coefficient of determination estimated from the log-linear regression model (T.sub.1/2; data not shown). The abuse quotient was obtained using the following expression AQ=C.sub.max/T.sub.max.

Results

[0128]

TABLE-US-00003 TABLE 2.1 Individual and mean values of AQ obtained for tramadol and O-desmethyltramadol after oral administration of 2 × 100 mg co-crystal E-58425 tablets (Treatment 1) to healthy subjects Tramadol O-desmethyltramadol C.sub.max AQ C.sub.max AQ (ng/ T.sub.max (ng/ (ng/ T.sub.max (ng/ Subject Period mL) (h) (mL .Math. h)) mL) (h) (mL .Math. h)) 1 2 179.23 4.00 44.81 34.93 6.00 5.82 2 1 226.56 8.00 28.32 87.98 8.00 11.00 3 3 224.21 3.00 74.74 53.69 3.00 17.90 4 4 306.70 2.62 117.06 47.51 3.50 13.57 5 4 175.24 3.50 50.07 41.10 4.00 10.28 6 3 105.36 4.00 26.34 71.18 4.00 17.80 7 1 143.59 4.00 35.90 36.17 4.00 9.04 8 2 250.44 2.50 100.18 89.32 3.50 25.52 9 4 207.46 4.00 51.87 37.53 4.00 9.38 10 2 136.31 6.00 22.72 55.51 6.00 9.25 11 1 180.00 3.50 51.43 44.29 4.00 11.07 12 3 194.45 1.75 111.11 50.68 8.00 6.34 13 4 245.13 2.50 98.05 59.24 2.50 23.70 14 3 247.60 3.50 70.74 43.30 6.00 7.22 15 1 318.15 3.53 90.13 71.03 3.53 20.12 16 2 205.79 3.00 68.60 67.64 3.50 19.33 18 1 254.85 3.50 72.81 76.39 3.00 25.46 19 3 200.88 2.50 80.35 49.74 6.00 8.29 20 4 136.40 3.50 38.97 25.88 3.50 7.39 21 1 263.95 3.00 87.98 61.08 4.00 15.27 22 3 256.94 3.00 85.65 39.87 6.00 6.65 23 4 202.08 3.00 67.36 31.18 6.00 5.20 24 2 214.14 2.50 85.66 43.41 3.00 14.47 25 4 103.91 1.25 83.13 65.22 3.50 18.64 26 3 364.28 3.50 104.08 72.02 4.00 18.00 27 2 217.71 4.00 54.43 57.73 6.00 9.62 28 1 162.44 2.50 64.98 45.65 4.00 11.41 29 4 257.07 3.00 85.69 55.55 4.00 13.89 30 2 319.22 3.00 106.41 64.67 6.00 10.78 31 3 166.56 2.50 66.62 39.97 3.00 13.32 33 1 156.84 3.00 52.28 55.41 4.00 13.85 35 2 174.33 3.00 58.11 62.53 3.50 17.87 36 3 272.96 3.00 90.99 61.11 3.50 17.46 n 33 33 33 33 33 33 Mean 214.3 3.3 70.5 54.5 4.4 13.5 Median 207.5 3.0 70.7 55.4 4.0 13.3 SD 62.1 1.2 25.5 15.6 1.4 5.7 CV (%) 29.0 35.4 36.1 28.5 32.3 42.0 SE 4.4 1.0

[0129] Subjects 17, 32 and 34 withdrew their consent or were withdrawn from the study

TABLE-US-00004 TABLE 2.2 Individual and mean values of AQ obtained for tramadol and O-desmethyltramadol after oral administration of 2 × 50 mg tramadol HCl tablets (Ultram ®), (Treatment 2) to healthy subjects Tramadol O-desmethyltramadol C.sub.max AQ C.sub.max AQ (ng/ T.sub.max (ng/ (ng/ T.sub.max (ng/ Subject Period mL) (h) (mL .Math. h)) mL) (h) (mL .Math. h)) 1 4 275.54 1.50 183.69 47 24 3.50 13.50 2 2 285.98 2.50 114 39 93.79 3.00 31.26 3 1 293.07 2.50 117.23 84.62 3.50 18.46 4 3 394.38 1.75 225.36 61.56 2.50 24.82 5 3 273.35 2.00 136.68 60.45 2.00 30.23 6 1 190.51 1.25 152.41 112.97 2.00 58.48 7 2 204.59 3.00 68.20 54.11 3.00 18.04 8 4 298.18 1.75 170.39 123.27 2.50 49.31 9 3 331.21 2.00 165.61 60.50 3.00 20.17 10 4 255.66 1.50 170.44 96.67 1.25 77.33 12 1 273.07 2.00 136.54 69.13 2.50 27.65 13 3 277.09 2.50 110 84 86.80 2.50 34 72 14 1 291.76 2.50 116.70 64.24 2.50 25.70 15 2 372.95 1.25 298.36 78.52 2.53 31.03 16 4 333.42 1.50 222.28 57.13 3.50 16.32 18 2 394.06 2.00 197.03 125.85 2.00 62.92 19 1 300.16 2.00 150.08 85.82 2.00 42.91 20 3 190.23 1.50 126.82 36.27 1.50 24.18 21 2 415.76 2.50 168 30 78.39 2.50 31.35 22 1 334.16 1.50 222.77 64.25 2.00 32.12 23 3 319.62 2.50 127.65 53.55 3.50 15.30 24 4 321.71 1.25 257.37 72.99 2.50 29.19 25 3 174.56 1.75 99.78 115.95 1.50 77.30 26 1 378.07 2.50 151.23 102.42 3.00 34.14 27 4 292.50 2.00 146.25 68.97 6.00 11.50 28 2 229.64 2.00 114.82 58.07 2.00 29.04 29 3 395.06 2.00 197.53 81.57 3.00 27.19 30 4 465.87 1.50 310.58 100.31 1.50 66.88 31 1 218.09 1.50 145.39 62.89 1.50 41.92 33 2 324.94 0.75 433.25 96.33 1.25 77.06 35 4 285.83 1.75 163.33 102.18 2.00 51 09 36 1 377.10 2.50 150.84 74.45 2.50 29.78 n 32 32 32 32 32 32 Mean 305.3 1.9 173.4 78.5 2.5 36.2 Median 295.6 2.0 151.8 73.7 2.5 30.6 SD 70.6 0.5 72.3 22.9 0.9 19.1 CV (%) 23.1 26.6 41.7 29.2 36.9 52.6 SE 12.8 3.45

[0130] Subjects 11, 17, 32 and 34 withdrew their consent or were withdrawn from the study

TABLE-US-00005 TABLE 2.3 Individual and mean values of AQ obtained for tramadol and O-desmethyltramadol after oral administration of 2 × 50 mg tramadol HCl tablets (Ultram ®) and 1 × 100 mg celecoxib capsule (Celebrex ®), (Treatment 4) to healthy subjects Tramadol O-desmethyltramadol C.sub.max AQ C.sub.max AQ (ng/ T.sub.max (ng/ (ng/ T.sub.max (ng/ Subject Period mL) (h) (mL .Math. h)) mL) (h) (mL .Math. h)) 1 1 267.76 1.25 214.21 52.60 3.00 17 53 2 3 331.19 2.00 165.60 90.06 3.50 25.73 3 4 276.09 2.50 110.44 76.05 3.00 25.02 4 2 373.85 2.00 186.93 62.55 2.50 25.02 5 2 296.43 2.00 148.22 68.77 2.00 34.38 6 4 193.76 2.00 96.88 112.69 2.00 56.35 7 3 250.01 2.00 125.01 57 33 2.50 22.93 8 1 350.74 1.50 233.83 125.29 1.50 83.52 9 2 287.00 1.50 191.33 70.86 2.00 35.44 10 1 221.30 2.50 88.52 89.66 1.25 71.72 11 3 266.67 2.00 133.34 71.36 2.00 35.68 13 2 329.98 1.50 219.99 71 82 1.50 47.88 14 4 356.89 1.50 237.93 47.68 2.00 23.84 15 3 362.70 1.75 207.26 76.98 2.50 30.79 16 1 277.99 2.00 139.00 84.30 2.50 33.72 18 3 378.74 1.50 252.49 135.81 2.00 67.90 19 4 340.45 1.00 340.45 74.15 2.50 29.66 20 2 183.99 1.50 122.66 36.56 1.75 20.89 21 3 371 22 3.00 123.74 69.61 4.00 17.40 22 4 392.02 1.50 261.35 54.10 2.50 21.64 23 2 346.39 2.00 173.20 53.63 3.00 17.88 24 1 304.72 2.00 152.36 79.84 2.50 31.93 25 2 194.35 1.25 155.48 112.05 1.50 74.70 26 4 465.57 2.00 232.79 96.57 2.50 38.63 27 1 323.08 1.50 215.39 74.52 3.00 24.84 28 3 347.87 1.28 271.77 65.66 8.00 8.21 29 2 320.68 2.50 128.27 72.37 2.50 28.95 30 1 438.45 1.26 350.76 103.69 1.75 59.25 31 4 211.89 3.00 70.63 58.13 3.00 19.38 33 3 313.18 1.00 313.18 86.13 1.75 49.22 35 1 325.70 1.75 186.11 106.36 1.75 60.78 36 4 294.15 6.00 49.03 66.99 6.00 11.17 n 32 32 32 32 32 32 Mean 312.3 1.9 184.3 78.2 2.6 36.0 Median 321.9 1.9 179.7 73.3 2.5 30.2 SD 67.7 0.9 75.0 22.9 1.3 19.7 CV (%) 21.7 46.3 40.7 29.3 50.8 54.6 SE 13.3 3.5

[0131] Subjects 12, 17, 32 and 34 withdrew their consent or were withdrawn from the study

TABLE-US-00006 TABLE 3 Summary of AQ obtained for tramadol and O-desmethyltramadol (M1) after oral administration of co-crystal E-58425 tablets, 2 × 50 mg tramadol HCl tablets (Ultram ®) and 2 × 50 mg tramadol HCl tablets (Ultram ®), and 1 × 100 mg celecoxib capsule (Celebrex ®) to healthy subjects Co-crystal Ultram.sup.R + E-58425 Ultram.sup.R Celebrex.sup.R AQ Mean SE Mean SE Mean SE Tramadol 70.5 4.4 173.4 12.8 184.3 13.3 M1 13.5 1.0 30.2 3.4 35.0 3.5

Embodiments

[0132] E1) A co-crystal of (rac)-tramadol.HCl and celecoxib, or a pharmaceutically acceptable derivatives thereof, for treating pain while reducing the abuse liability of (the) tramadol. [0133] E2) The co-crystal for use according to embodiment E1), wherein the molecular ratio between the (rac)-tramadol.HCl and celecoxib is 1:1. [0134] E3) The co-crystal for use according to any one of embodiments E1) or E2) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with at least one of the peaks [2θ] selected from 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0135] E4) The co-crystal for use according to any one of embodiments E2) or E3), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0136] 14.1 and 22.7[°], [0137] 14.1 and 19.0[°], [0138] 14.1 and 16.8[°], [0139] 16.8 and 22.7[°]. [0140] 16.8 and 19.0[°], or [0141] 19.0 and 22.7[°], [0142] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0143] E5) The co-crystal for use according to any one of embodiments E2) to E4), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0144] 14.1, 16.8 and 22.7[°], [0145] 14.1, 19.0 and 22.7[°], [0146] 14.1, 16.8 and 19.0[°], or [0147] 16.8, 19.0 and 22.7[°], [0148] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0149] E6) The co-crystal for use according to any one of embodiments E2) to E5), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0 and 22.7[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0150] E7) The co-crystal for use according to embodiment E6), characterized in that the co-crystal shows additional peaks [2θ] at 7.1, 19.9 and 20.5[°]. [0151] E8) The co-crystal for use according to embodiment E7), characterized in that the co-crystal shows additional peaks [2θ] at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4 and 26.1 [°]. [0152] E9) The co-crystal for use according to any one of embodiments E1) to E8) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0153] E10) The co-crystal for use according to any one of embodiments E1) to E9) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Fourier Transform Infra Red pattern with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m) 625.9 (m) cm-1. [0154] E11) The co-crystal for use according to any one of embodiments E1) to E10) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal has an orthorhombic unit cell with the following dimensions: [0155] a=11.0323(7) Å [0156] b=18.1095(12) Å [0157] c=17.3206(12) Å. [0158] E12) The co-crystal for use according to any one of embodiments E1) to E11) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that for the co-crystal the endothermic sharp peak corresponding to the melting point has an onset at 164° C. [0159] E13) The co-crystal for use according to any one of embodiments E1) to E12), for the treatment of acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe to moderate pain, hyperalgesia, pain related to central sensitization, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy and osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica. [0160] E14) The co-crystal for use according to any one of embodiments E1) to E13), for the treatment of acute and chronic moderate to severe pain, acute moderate to severe pain, acute moderate pain, acute severe pain, chronic moderate to severe pain, chronic moderate pain, or chronic severe pain. [0161] E15) The co-crystal for use according to any one of embodiments E1) to E14) wherein the co-crystal is comprised in a pharmaceutical composition also comprising at least a solubility enhancer polymer; wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or from copovidone, povidone, cyclodextrin, polyethylene glycol and lauroyl macrogol-32 glycerides EP, preferably wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or other hydrophilic polymers selected from copovidone, or povidone, most preferably wherein the solubility enhancer polymer is copovidone. [0162] E21) A co-crystal of (rac)-tramadol.HCl and celecoxib, or a pharmaceutically acceptable derivatives thereof, for treating pain and preventing an addiction to tramadol. [0163] E22) The co-crystal for use according to embodiment E21), wherein the molecular ratio between the (rac)-tramadol.HCl and celecoxib is 1:1. [0164] E23) The co-crystal for use according to any one of embodiments E21) or E22) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with at least one of the peaks [2θ] selected from 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0165] E24) The co-crystal for use according to any one of embodiments E22) or E23), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0166] 14.1 and 22.7[°], [0167] 14.1 and 19.0[°], [0168] 14.1 and 16.8[°], [0169] 16.8 and 22.7[°]. [0170] 16.8 and 19.0[°], or [0171] 19.0 and 22.7[°], [0172] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0173] E25) The co-crystal for use according to any one of embodiments E22) to E24), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0174] 14.1, 16.8 and 22.7[°], [0175] 14.1, 19.0 and 22.7[°]. [0176] 14.1, 16.8 and 19.0[°], or [0177] 16.8, 19.0 and 22.7[°], [0178] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0179] E26) The co-crystal for use according to any one of embodiments E22) to E25), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0 and 22.7[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0180] E27) The co-crystal for use according to embodiment E26), characterized in that the co-crystal shows additional peaks [2θ] at 7.1, 19.9 and 20.5[°]. [0181] E28) The co-crystal for use according to embodiment E27), characterized in that the co-crystal shows additional peaks [2θ] at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4 and 26.1 [°]. [0182] E29) The co-crystal for use according to any one of embodiments E21) to E28) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0183] E30) The co-crystal for use according to any one of embodiments E21) to E29) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Fourier Transform Infra Red pattern with absorption bends at 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m) 625.9 (m) cm-1. [0184] E31) The co-crystal for use according to any one of embodiments E21) to E30) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal has an orthorhombic unit cell with the following dimensions: [0185] a=11.0323(7) Å [0186] b=18.1095(12) Å [0187] c=17.3206(12) Å. [0188] E32) The co-crystal for use according to any one of embodiments E21) to E31) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that for the co-crystal the endothermic sharp peak corresponding to the melting point has an onset at 164° C. [0189] E33) The co-crystal for use according to any one of embodiments E21) to E32), for the treatment of acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe to moderate pain, hyperalgesia, pain related to central sensitization, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy and osteoarthritis, fibromyalgia: rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica. [0190] E34) The co-crystal for use according to any one of embodiments E21) to E33), for the treatment of acute and chronic moderate to severe pain, acute moderate to severe pain, acute moderate pain, acute severe pain, chronic moderate to severe pain, chronic moderate pain, or chronic severe pain. [0191] E35) The co-crystal for use according to any one of embodiments E21) to E34) wherein the co-crystal is comprised in a pharmaceutical composition also comprising at least a solubility enhancer polymer; wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or from copovidone, povidone, cyclodextrin, polyethylene glycol and lauroyl macrogol-32 glycerides EP, preferably wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or other hydrophillic polymers selected from copovidone, or povidone, most preferably wherein the solubility enhancer polymer is copovidone. [0192] E41) A co-crystal of (rac)-tramadol.HCl and celecoxib, or a pharmaceutically acceptable derivatives thereof, for treating pain, preventing the risk of an addiction to tramadol. [0193] E42) The co-crystal for use according to embodiment E41), wherein the molecular ratio between the (rac)-tramadol.HCl and celecoxib is 1:1. [0194] E43) The co-crystal for use according to any one of embodiments E41) or E42) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with at least one of the peaks [2θ] selected from 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 38.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0195] E44) The co-crystal for use according to any one of embodiments E42) or E43), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0196] 14.1 and 22.7[°], [0197] 14.1 and 19.0[°], [0198] 14.1 and 16.8[°], [0199] 16.8 and 22.7[°]. [0200] 16.8 and 19.0[°], or [0201] 19.0 and 22.7[°], [0202] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0203] E45) The co-crystal for use according to any one of embodiments E42) to E44), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å) at: [0204] 14.1, 16.8 and 22.7[°], [0205] 14.1, 19.0 and 22.7[°], [0206] 14.1, 16.8 and 19.0[°], or [0207] 16.8, 19.0 and 22.7[°], [0208] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0209] E46) The co-crystal for use according to any one of embodiments E42) to E45), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0 and 22.7[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0210] E47) The co-crystal for use according to embodiment E46), characterized in that the co-crystal shows additional peaks [2θ] at 7.1, 19.9 and 20.5[°]. [0211] E48) The co-crystal for use according to embodiment E47), characterized in that the co-crystal shows additional peaks [2θ] at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4 and 26.1 [°]. [0212] E49) The co-crystal for use according to any one of embodiments E41) to E48) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2. 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0213] E50) The co-crystal for use according to any one of embodiments E41) to E49) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Fourier Transform Infra Red pattern with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m) 625.9 (m) cm-1. [0214] E51) The co-crystal for use according to any one of embodiments E41) to E50) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal has an orthorhombic unit cell with the following dimensions: [0215] a=11.0323(7) Å [0216] b=18.1095(12) Å [0217] c=17.3206(12) Å. [0218] E52) The co-crystal for use according to any one of embodiments E41) to E51) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that for the co-crystal the endothermic sharp peak corresponding to the melting point has an onset at 164° C. [0219] E53) The co-crystal for use according to any one of embodiments E41) to E52), for the treatment of acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe to moderate pain, hyperalgesia, pain related to central sensitization, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy and osteoarthritis, fibromyalgia: rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica. [0220] E54) The co-crystal for use according to any one of embodiments E41) to E53), for the treatment of acute and chronic moderate to severe pain, acute moderate to severe pain, acute moderate pain, acute severe pain, chronic moderate to severe pain, chronic moderate pain, or chronic severe pain. [0221] E55) The co-crystal for use according to any one of embodiments E41) to E54) wherein the co-crystal is comprised in a pharmaceutical composition also comprising at least a solubility enhancer polymer; wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or from copovidone, povidone, cyclodextrin, polyethylene glycol and lauroyl macrogol-32 glycerides EP, preferably wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or other hydrophilic polymers selected from copovidone, or povidone, most preferably wherein the solubility enhancer polymer is copovidone. [0222] E61) A co-crystal of (rac)-tramadol.HCl and celecoxib, or a pharmaceutically acceptable derivatives thereof, for treating pain in a patient with an addiction to tramadol or the risk of it. [0223] E62) The co-crystal for use according to embodiment E61), wherein the molecular ratio between the (rac)-tramadol.HCl and celecoxib is 1:1. [0224] E63) The co-crystal for use according to any one of embodiments E61) or E62) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with at least one of the peaks [2θ] selected from 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0225] E64) The co-crystal for use according to any one of embodiments E62) or E63), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0226] 14.1 and 22.7[°], [0227] 14.1 and 19.0[°], [0228] 14.1 and 16.8[°], [0229] 16.8 and 22.7[°], [0230] 16.8 and 19.0[°], or [0231] 19.0 and 22.7[°], [0232] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0233] E65) The co-crystal for use according to any one of embodiments E62) to E64), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0234] 14.1, 16.8 and 22.7[°]. [0235] 14.1, 19.0 and 22.7[°]. [0236] 14.1, 16.8 and 19.0[°], or [0237] 16.8, 19.0 and 22.7[°], [0238] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0239] E66) The co-crystal for use according to any one of embodiments E62) to E65), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0 and 22.7[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0240] E67) The co-crystal for use according to embodiment E66), characterized in that the co-crystal shows additional peaks [2θ] at 7.1, 19.9 and 20.5[°]. [0241] E68) The co-crystal for use according to embodiment E67), characterized in that the co-crystal shows additional peaks [2θ] at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4 and 26.1[°]. [0242] E69) The co-crystal for use according to any one of embodiments E61) to E68) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0243] E70) The co-crystal for use according to any one of embodiments E61) to E69) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Fourier Transform Infra Red pattern with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m) 625.9 (m) cm-1. [0244] E71) The co-crystal for use according to any one of embodiments E61) to E70) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal has an orthorhombic unit cell with the following dimensions: [0245] a=11.0323(7) Å [0246] b=18.1095(12) Å [0247] c=17.3206(12) Å. [0248] E72) The co-crystal for use according to any one of embodiments E61) to E71) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that for the co-crystal the endothermic sharp peak corresponding to the melting point has an onset at 164° C. [0249] E73) The co-crystal for use according to any one of embodiments E61) to E72), for the treatment of acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe to moderate pain, hyperalgesia, pain related to central sensitization, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy and osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica. [0250] E74) The co-crystal for use according to any one of embodiments E61) to E73), for the treatment of acute and chronic moderate to severe pain, acute moderate to severe pain, acute moderate pain, acute severe pain, chronic moderate to severe pain, chronic moderate pain, or chronic severe pain. [0251] E75) The co-crystal for use according to any one of embodiments E61) to E74) wherein the co-crystal is comprised in a pharmaceutical composition also comprising at least a solubility enhancer polymer; wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or from copovidone, povidone, cyclodextrin, polyethylene glycol and lauroyl macrogol-32 glycerides EP, preferably wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or other hydrophilic polymers selected from copovidone, or povidone, most preferably wherein the solubility enhancer polymer is copovidone. [0252] E81) A co-crystal of (rac)-tramadol.HCl and celecoxib, or a pharmaceutically acceptable derivatives thereof, for treating pain and inhibiting, delaying, reducing or reversing addiction to tramadol. [0253] E82) The co-crystal for use according to embodiment E81), wherein the molecular ratio between the (rac)-tramadol.HCl and celecoxib is 1:1. [0254] E83) The co-crystal for use according to any one of embodiments E81) or E82) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with at least one of the peaks [2θ] selected from 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0255] E84) The co-crystal for use according to any one of embodiments E82) or E83), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0256] 14.1 and 22.7[°]. [0257] 14.1 and 19.0[°], [0258] 14.1 and 16.8[°], [0259] 16.8 and 22.7[°], [0260] 16.8 and 19.0[°], or [0261] 19.0 and 22.7[°], [0262] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0263] E85) The co-crystal for use according to any one of embodiments E82) to E84), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0264] 14.1, 16.8 and 22.7[°], [0265] 14.1, 19.0 and 22.7[°], [0266] 14.1, 16.8 and 19.0[°], or [0267] 16.8, 19.0 and 22.7[°], [0268] with the 2D values being obtained using copper radiation (CuKα1 1.54060 Å). [0269] E86) The co-crystal for use according to any one of embodiments E82) to E85), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0 and 22.7[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0270] E87) The co-crystal for use according to embodiment E86), characterized in that the co-crystal shows additional peaks [2θ] at 7.1, 19.9 and 20.5[°]. [0271] E88) The co-crystal for use according to embodiment E87), characterized in that the co-crystal shows additional peaks [2θ] at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4 and 26.1[°]. [0272] E89) The co-crystal for use according to any one of embodiments E81) to E88) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0273] E90) The co-crystal for use according to any one of embodiments E81) to E89) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Fourier Transform Infra Red pattern with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m) 625.9 (m) cm-1. [0274] E91) The co-crystal for use according to any one of embodiments E81) to E90) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal has an orthorhombic unit cell with the following dimensions: [0275] a=11.0323(7) Å [0276] b=18.1095(12) Å [0277] c=17.3206(12) Å. [0278] E92) The co-crystal for use according to any one of embodiments E81) to E91) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that for the co-crystal the endothermic sharp peak corresponding to the melting point has an onset at 164° C. [0279] E93) The co-crystal for use according to any one of embodiments E81) to E92), for the treatment of acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe to moderate pain, hyperalgesia, pain related to central sensitization, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy and osteoarthritis, fibromyalgia: rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica. [0280] E94) The co-crystal for use according to any one of embodiments E81) to E93), for the treatment of acute and chronic moderate to severe pain, acute moderate to severe pain, acute moderate pain, acute severe pain, chronic moderate to severe pain, chronic moderate pain, or chronic severe pain. [0281] E95) The co-crystal for use according to any one of embodiments E81) to E94) wherein the co-crystal is comprised in a pharmaceutical composition also comprising at least a solubility enhancer polymer; wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or from copovidone, povidone, cyclodextrin, polyethylene glycol and lauroyl macrogol-32 glycerides EP, preferably wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or other hydrophilic polymers selected from copovidone, or povidone, most preferably wherein the solubility enhancer polymer is copovidone. [0282] E101) A co-crystal of (rac)-tramadol.HCl and celecoxib, or a pharmaceutically acceptable derivatives thereof, for treating pain and reducing the incidence of addiction to tramadol. [0283] E102) The co-crystal for use according to embodiment E101), wherein the molecular ratio between the (rac)-tramadol.HCl and celecoxib is 1:1. [0284] E103) The co-crystal for use according to any one of embodiments E101) or E102) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with at least one of the peaks [2θ] selected from 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0285] E104) The co-crystal for use according to any one of embodiments E102) or E103), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0286] 14.1 and 22.7[°], [0287] 14.1 and 19.0[°], [0288] 14.1 and 16.8[°]. [0289] 16.8 and 22.7[°], [0290] 16.8 and 19.0[°], or [0291] 19.0 and 22.7[°]. [0292] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0293] E105) The co-crystal for use according to any one of embodiments E102) to E104), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0294] 14.1, 16.8 and 22.7[°], [0295] 14.1, 19.0 and 22.7[°], [0296] 14.1, 16.8 and 19.0[°], or [0297] 16.8, 19.0 and 22.7[°]. [0298] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0299] E106) The co-crystal for use according to any one of embodiments E102) to E105), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0 and 22.7[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0300] E107) The co-crystal for use according to embodiment E106), characterized in that the co-crystal shows additional peaks [2θ] at 7.1, 19.9 and 20.5[°]. [0301] E108) The co-crystal for use according to embodiment E107), characterized in that the co-crystal shows additional peaks [2θ] at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4 and 26.1 [°]. [0302] E109) The co-crystal for use according to any one of embodiments E101) to E108) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0303] E110) The co-crystal for use according to any one of embodiments E101) to E109) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Fourier Transform Infra Red pattern with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m) 625.9 (m) cm-1. [0304] E111) The co-crystal for use according to any one of embodiments E101) to E110) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal has an orthorhombic unit cell with the following dimensions: [0305] a=11.0323(7) Å [0306] b=18.1095(12) Å [0307] c=17.3206(12) Å. [0308] E112) The co-crystal for use according to any one of embodiments E101) to E111) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that for the co-crystal the endothermic sharp peak corresponding to the melting point has an onset at 164° C. [0309] E113) The co-crystal for use according to any one of embodiments E101) to E112), for the treatment of acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe to moderate pain, hyperalgesia, pain related to central sensitization, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy and osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica. [0310] E114) The co-crystal for use according to any one of embodiments E101) to E113), for the treatment of acute and chronic moderate to severe pain, acute moderate to severe pain, acute moderate pain, acute severe pain, chronic moderate to severe pain, chronic moderate pain, or chronic severe pain. [0311] E115) The co-crystal for use according to any one of embodiments E101) to E114) wherein the co-crystal is comprised in a pharmaceutical composition also comprising at least a solubility enhancer polymer; wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or from copovidone, povidone, cyclodextrin, polyethylene glycol and lauroyl macrogol-32 glycerides EP, preferably wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or other hydrophilic polymers selected from copovidone, or povidone, most preferably wherein the solubility enhancer polymer is copovidone. [0312] E121) A co-crystal of (rac)-tramadol.HCl and celecoxib, or a pharmaceutically acceptable derivatives thereof, for treating pain and reducing the likelihood that the treatment will cause an addiction to tramadol. [0313] E122) The co-crystal for use according to embodiment E121), wherein the molecular ratio between the (rac)-tramadol.HCl and celecoxib is 1:1. [0314] E123) The co-crystal for use according to any one of embodiments E121) or E122) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with at least one of the peaks [2θ] selected from 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0315] E124) The co-crystal for use according to any one of embodiments E122) or E123), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0316] 14.1 and 22.7[°], [0317] 14.1 and 19.0[°], [0318] 14.1 and 16.8[°], [0319] 16.8 and 22.7[°], [0320] 16.8 and 19.0[°], or [0321] 19.0 and 22.7[°], [0322] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0323] E125) The co-crystal for use according to any one of embodiments E122) to E124), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at: [0324] 14.1, 16.8 and 22.7[°], [0325] 14.1, 19.0 and 22.7[°], [0326] 14.1, 16.8 and 19.0[°], or [0327] 16.8, 19.0 and 22.7[°]. [0328] with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0329] E126) The co-crystal for use according to any one of embodiments E122) to E125), characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 14.1, 16.8, 19.0 and 22.7[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0330] E127) The co-crystal for use according to embodiment E126), characterized in that the co-crystal shows additional peaks [2θ] at 7.1, 19.9 and 20.5[°]. [0331] E128) The co-crystal for use according to embodiment E127), characterized in that the co-crystal shows additional peaks [2θ] at 13.6, 13.9, 17.5, 18.0, 19.5, 21.2, 21.3, 21.8, 22.6, 23.6, 24.1, 24.4 and 26.1 [°]. [0332] E129) The co-crystal for use according to any one of embodiments E121) to E128) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2θ] at 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2[°], with the 2θ values being obtained using copper radiation (CuKα1 1.54060 Å). [0333] E130) The co-crystal for use according to any one of embodiments E121) to E129) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal shows a Fourier Transform Infra Red pattern with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1338.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m) 625.9 (m) cm-1. [0334] E131) The co-crystal for use according to any one of embodiments E121) to E130) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that the co-crystal has an orthorhombic unit cell with the following dimensions: [0335] a=11.0323(7) Å [0336] b=18.1095(12) Å [0337] c=17.3206(12) Å. [0338] E132) The co-crystal for use according to any one of embodiments E121) to E131) comprising (rac)-tramadol.HCl and celecoxib in a molecular ratio of 1:1, characterized in that for the co-crystal the endothermic sharp peak corresponding to the melting point has an onset at 164° C. [0339] E133) The co-crystal for use according to any one of embodiments E121) to E132), for the treatment of acute pain, chronic pain, neuropathic pain, nociceptive pain, mild and severe to moderate pain, hyperalgesia, pain related to central sensitization, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy and osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica. [0340] E134) The co-crystal for use according to any one of embodiments E121) to E133), for the treatment of acute and chronic moderate to severe pain, acute moderate to severe pain, acute moderate pain, acute severe pain, chronic moderate to severe pain, chronic moderate pain, or chronic severe pain. [0341] E135) The co-crystal for use according to any one of embodiments E121) to E134) wherein the co-crystal is comprised in a pharmaceutical composition also comprising at least a solubility enhancer polymer; wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or from copovidone, povidone, cyclodextrin, polyethylene glycol and lauroyl macrogol-32 glycerides EP, preferably wherein the solubility enhancer polymer is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or other hydrophilic polymers selected from copovidone, or povidone, most preferably wherein the solubility enhancer polymer is copovidone.