doi:10.1016/j.pbb.2005.07.016 
Copyright © 2005 Elsevier Inc. All rights reserved.
Evaluation of pain-related behavior, bone destruction and effectiveness of fentanyl, sufentanil, and morphine in a murine model of cancer pain
Mohammed El Mouedden
, 
and Theo Frans Meert
Johnson & Johnson Pharmaceutical Research & Development a Division of Janssen Pharmaceutica N. V., Turnhoutseweg 30, B2340 Beerse, Belgium
Received 15 March 2005;
revised 8 July 2005;
accepted 20 July 2005.
Available online 25 August 2005.
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Abstract
The present study was conducted to evaluate the pain development and bone destruction during bone cancer growth in a murine model of bone cancer pain and to evaluate the analgesic efficacy of fentanyl, sufentanil, and morphine in this model. C3H/HeNCrl mice were inoculated into the intramedullary space of the femur with osteolytic NCTC 2472 fibrosarcoma cells, and followed during a 3-week period to assess pain behaviors (spontaneous lifting and limb-use during forced ambulation on rotarod) and bone destruction (parameters indicative of bone lesions determined by μCT-scans of the tumor-bearing bones) during bone cancer growth. The results showed that in this murine model of cancer-induced bone pain, behavioural manifestations of pain emerge in parallel with the progression of bone destruction. The subcutaneous administration of fentanyl (0.025–0.64 mg/kg), sufentanil (0.005–0.04 mg/kg), and morphine (2.5–40 mg/kg) on the test days 15 and 22 post-inoculation reduced pain-related behaviors in a dose dependent manner. A complete relief from pain-related behaviors was achieved with the following doses: ≥ 0.16 mg/kg fentanyl, 0.02 mg/kg sufentanil, and 20 mg/kg morphine. In conclusion, the results showed a clear link between tumor growth-induced bone destruction and behavioral pain manifestations, the latter was effectively controlled by the opioids fentanyl, sufentanil, and morphine.
Keywords: Bone cancer; Cancer pain; Fentanyl; Morphine; Sufentanil; Opioid; Murine model; Osteolysis; CT-scan; Trabecular bone structure
Fig. 1. Time-course of the development of spontaneous lifting and ambulatory limb-use on rotarod in sham and NCTC 2472 sarcoma-injected animals (n = 6/group). Percentage of time lifting (A) and limb-use on rotarod scores (B) were measured in animal groups prior to and 7, 12, 15, 18, and 22 days after inoculation. Values are expressed as mean ± S.E.M. Data were analyzed by one-way analysis of variance (ANOVA), followed by the Mann–Whitney U test. *Significantly different from sham value.
Fig. 2. Three-dimensional μCT re-construction images of the NCTC 2472 sarcoma-injected distal femur in different animal prior to and 7, 12, 15, 18, and 22 days after inoculation. In the animal prior injection (day 0), no bone destruction or bone formation was observed. At 12 (day 12) days after tumor injection, there was a clear bone destruction in tumor-bearing femoral bones. Note the extreme bone destruction with some new bone formation (arrow) in sarcoma-injected animals at day 15 (day 15) and 18 (day 18) after tumor implantation with pathological fractures frequently occurring by day 22 (day 22).
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Fig. 3. Microcomputed tomography parameter measurements in the NCTC 2472 sarcoma-injected distal femur of different groups prior to and 7, 12, 15, 18, and 22 days after inoculation (n = 6/group). The 4 μm region under the patella from distal left femurs in different groups was used for 2- and 3-dimensional analysis. In a 2-dimensional analysis, average of bone fragment area (Av.Obj.Ar, B) decrease and mean number of bone fragment (Obj.N, A) increase indicate bone osteolysis and fragmentation. In a 3-dimensional analysis, bone surface to volume ratio (BS/BV, C) increase indicates bone fragmentation in tumor-bearing animals, while decreased trabecular thickness (Tb.Th., D), and trabecular number (Tb.N., E), bone volume (BV, F) indicate reduction of bone thickness due to tumor-induced osteolysis in tumor-bearing animals. Values are expressed as mean ± S.E.M. Data were analyzed by one-way analysis of variance (ANOVA), followed by the Mann–Whitney U test. *Significantly different from sham value.
Fig. 4. Correlation between bone destruction parameters and bone cancer-related pain behavior in different groups (n = 6/group) prior to and 7, 12, 15, 18, and 22 days after inoculation of the femur with NCTC 2472 sarcoma cells. Spontaneous lifting was plotted against μCT parameters, mean number of bone fragments (Obj.N.), bone surface to volume ratio (BS/BV) increase indicates bone fragmentation in tumor-bearing animals, while decreased average of bone fragment area (Avg.Obj.Ar) trabecular thickness (Tb.Th.), bone volume (BV), trabecular number (Tb.N.), and trabecular separation (Tb.Sp.) indicate reduction of bone thickness. Curvilinear polynomial functions were fitted by GraphPad software (for Panel A, R = 0.95, P < 0.0001; for Panel B, R = 0.9, P < 0.0001; for Panel C, R = 0.94, P < 0.0001; for Panel D, R = 0.82, P < 0.0001; for Panel E, R = 0.94, P < 0.0001; for Panel F, R = 0.77, P < 0.0001).
Fig. 5. Correlation between bone destruction parameters and bone cancer-related paw use impairment on rotarod in different groups (n = 6/group) prior to and 7, 12, 15, 18, and 22 days after inoculation of the femur with NCTC2472 sarcoma cells. Rotarod scores were plotted against μCT parameters, mean number of bone fragments (Obj.N.), bone surface to volume ratio (BS/BV) increase indicates bone fragmentation in tumor-bearing animals, while decreased trabecular thickness (Tb.Th.), bone volume (BV), trabecular number (Tb.N.), and trabecular separation (Tb.Sp.) indicate reduction of bone thickness. Curvilinear polynomial functions were fitted by GraphPad software (for Panel A, R = 0.85, P < 0.0001; for Panel B, R = 0.83, P < 0.0001; for Panel C, R = 0.77, P < 0.0001; for Panel D, R = 0.87, P < 0.0001; Panel E, R = 0.60, P < 0.0001; Panel F, R = 0.79, P < 0.0001).
Fig. 6. Dose-dependent effect of fentanyl, sufentanil, and morphine on bone cancer-related spontaneous paw lifting behavior in NCTC 2472 sarcoma-injected animals (n = 6/group). Percentage of time lifting was measured after 1 h in tumor-bearing animals treated subcutaneously with different doses of fentanyl (0.02–0.63 mg/kg s.c.), sufentanil (0.005–0.04 mg/kg s.c.), and morphine (2.5–40 mg/kg s.c.) on day 15, and 22 after tumor inoculation. Values are expressed as mean ± S.E.M. Data were analyzed by one-way analysis of variance (ANOVA), followed by the Mann–Whitney U test. *Significantly different from sham value.
Fig. 7. Dose-dependent effect of fentanyl, sufentanil, and morphine on bone cancer-related paw-impairment behavior in NCTC 2472 sarcoma-injected animals (n = 6/group). Limb-use on rotarod was scored after 1 h in tumor-bearing animals treated subcutaneously with different doses of fentanyl (0.02–0.63 mg/kg s.c.), sufentanil (0.005–0.04 mg/kg s.c.), and morphine (2.5–40 mg/kg s.c.) on days 15 and 22 after tumor inoculation. Values are expressed as mean ± S.E.M. Data were analyzed by one-way analysis of variance (ANOVA), followed by the Mann–Whitney U test. *Significantly different from sham value.
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